DIR LABORATORY

DIR LABORATORY

DNA METHYLATION

A
fB
Ac
C

DNA methylation is a key epigenetic mechanism implicated in transcriptional regulation, normal cellular development, and function. The addition of methyl groups that occurs mostly within CpG dinucleotides is catalyzed by three major DNA methyltransferase (DNMT) family members: DNMT1, DNMT3a, and DNMT3b.
CpG dinucleotides, which are under-represented in the genome, are concentrated in CpG islands (CGI). While most CpGs in the genome are methylated, CGI are not. Importantly, most CGI are located within promoter and transcription start sites of protein coding genes the expression of which is influenced by the methylation status of those CGI. As a matter of fact, methylated CGI are associated with silenced genes whereas unmethylated CGI are associated with expressed genes.

It is commonly known that inactivation of certain tumor-suppressor genes occurs as a consequence of abnormal DNA methylation within the promoter regions and numerous studies have demonstrated a broad range of genes silenced by DNA methylation in different cancer types. Global hypomethylation, instead, contributes to cell transformation by inducing genomic instability. In addition to alterations in promoter regions and repetitive DNA sequences, DNA methylation is also associated with transcriptional regulation of noncoding RNAs that could play a role in tumor suppression. Unlike genetic alterations, DNA methylation is reversible. The reversible nature of DNA methylation makes it an attractive therapeutic target along with providing a dynamic biomarker for prognostic use to follow disease progression.
D
E

DNA METHYLATION

A
fB
Ac
C

DNA methylation is a key epigenetic mechanism implicated in transcriptional regulation, normal cellular development, and function. The addition of methyl groups that occurs mostly within CpG dinucleotides is catalyzed by three major DNA methyltransferase (DNMT) family members: DNMT1, DNMT3a, and DNMT3b.
CpG dinucleotides, which are under-represented in the genome, are concentrated in CpG islands (CGI). While most CpGs in the genome are methylated, CGI are not. Importantly, most CGI are located within promoter and transcription start sites of protein coding genes the expression of which is influenced by the methylation status of those CGI. As a matter of fact, methylated CGI are associated with silenced genes whereas unmethylated CGI are associated with expressed genes.

It is commonly known that inactivation of certain tumor-suppressor genes occurs as a consequence of abnormal DNA methylation within the promoter regions and numerous studies have demonstrated a broad range of genes silenced by DNA methylation in different cancer types. Global hypomethylation, instead, contributes to cell transformation by inducing genomic instability. In addition to alterations in promoter regions and repetitive DNA sequences, DNA methylation is also associated with transcriptional regulation of noncoding RNAs that could play a role in tumor suppression. Unlike genetic alterations, DNA methylation is reversible. The reversible nature of DNA methylation makes it an attractive therapeutic target along with providing a dynamic biomarker for prognostic use to follow disease progression.
D
E

Our goal is to design RNA-based platforms to control DNA methylation

JOIN US
Linkedin Instagram Facebook X-twitter

#sciencebringspeopletogether

Our goal is to design RNA-based platforms to control DNA methylation

JOIN US
Linkedin Instagram Facebook X-twitter

#sciencebringspeopletogether

ABOUT

Dr. Annalisa Di Ruscio is an Assistant Professor in Medicine in the division of Hematology-Oncology, Beth Israel Deaconess Medical Center, at Harvard Medical School.
She received her MD from the Università Cattolica Sacro Cuore (UCSC), Rome. While completing the Hematology fellowship she moved to Boston to join Prof. Tenen’s group at Harvard Medical School, and started working on long non-coding RNAs. Upon completion of the clinical fellowship she pursued a PhD program in molecular biology and then continued as a post-doctoral fellow in Prof. Tenen’s laboratory. Here, she discovered a class of novel RNAs, termed DNA methyltransferase 1 (DNMT1)-interacting RNAs (DiRs) (Di Ruscio, Ebralidze et al. Nature, 2013), that play a key role in controlling cell type-specific DNA methylation patterns. This discovery defined a paradigm shift on the existing view on DNA methylation establishment offering a trailblazing perspective on the relationship between transcription and DNA methylation.

The main focus of Dr. Di Ruscio laboratory is to understand the impact of transcriptional activity in the establishment of epigenetic marks and to define the translational potential of RNAs as a tool to correct aberrant DNA methylation and other epigenetic marks (Ebralidze AK et al. preprint).
As aberrant DNA methylation is one of the most common molecular lesions in cancer cells, Di Ruscio’s group investigates the functional role of DiRs in myeloid disorders that are characterized by abnormal DNA methylation profile, such as Myelodysplastic Syndromes (MDS) and MDS evolution to Acute Myeloid Leukemia.
Using a pioneering approach, Di Ruscio’s group is developing DiR-mimicking platforms to correct DNA methylation profile globally and selectively in hematological and rare genetic conditions. The overarching goal of their studies is to generate RNA-guided gene-specific demethylating agents and overcome the toxicity and lack of specificity of currently approved hypomethylating therapies, with great benefit for patients’ quality of life and standard of cure  (Liu Y et al. preprint, Esposito, CL et al.).
More recently, Dr. Di Ruscio laboratory has started diving into understanding  the potential role of nicotinamide adenine dinucleotide (NAD) on DNA methylation and implication on normal and leukaemic  hematopoietic differentiation (Ummarino et al. 2021).

OUR PROJECTS

RNA-guided DNMT1 modulation

AGO2-mediated gene activation

AGO2-selective approach

Hematopoiesis & leukemia

Immune cell reprogramming

AptaDiR

Non-covalent and selective inhibition of DNMT1 may be achieved by aptamers. As a single-stranded DNA or RNA, an aptamer is the same type of molecule as the substrates for DNMT1, providing the possibility of competitive binding. Thus, an aptamer that can bind to a specific DNMT stronger than its native substrates, could inhibit its activity selectively via preventing the enzyme-substrate binding. Compared with the protein-based therapeutics, aptameric drugs are easier to be stored, handled, and modified to fit for medical applications; and can penetrate through biological barriers more easily, as well as possess much-reduced immunogenicity with low toxicity, presenting good promises for disease treatment. “Systematic Evolution of Ligands by EXponential enrichment” (SELEX) can help the discover of AptaDiR against DNMT1.

captaDiR

CaptaDiR is a next-generation RNA platform designed to achieve gene-specific DNA demethylation. Building upon the AptaDiR technology, CaptaDiR combines a DNMT1-interacting RNA domain with an additional sequence capable of recognizing a specific genomic target, generating a programmable chimeric RNA molecule. By coupling sequence recognition with selective epigenetic modulation, CaptaDiR is designed to enable targeted gene reactivation while preserving the native genomic architecture. This approach expands the versatility of RNA-based epigenetic therapeutics and provides a framework for precise regulation of disease-associated genes.

saRNA

Small activating RNAs (saRNAs) are double-stranded RNAs that increase the transcription of specific target genes. They function through an AGO2-dependent mechanism, whereby the RNA is loaded onto AGO2, transported into the nucleus, and directed to its genomic target to promote transcriptional activation. Our research focuses on a synthetic saRNA, AW1-51, targeting CEBPA, a key regulator of granulopoiesis, monopoiesis, lung development and liver function. Aberrant DNA methylation and reduced CEBPA expression have been associated with several diseases, including acute myeloid leukemia and lung cancer. Using leukemia and lung cancer models, we investigate whether AW1-51 promotes gene activation by acting as a DiR-mimicking molecule capable of reshaping the epigenetic landscape of the CEBPA locus and nearby regulatory elements.

ABOUT

Dr. Annalisa Di Ruscio is an Assistant Professor in Medicine in the division of Hematology-Oncology, Beth Israel Deaconess Medical Center, at Harvard Medical School.
She received her MD from the Università Cattolica Sacro Cuore (UCSC), Rome. While completing the Hematology fellowship she moved to Boston to join Prof. Tenen’s group at Harvard Medical School, and started working on long non-coding RNAs. Upon completion of the clinical fellowship she pursued a PhD program in molecular biology and then continued as a post-doctoral fellow in Prof. Tenen’s laboratory. Here, she discovered a class of novel RNAs, termed DNA methyltransferase 1 (DNMT1)-interacting RNAs (DiRs) (Di Ruscio, Ebralidze et al. Nature, 2013), that play a key role in controlling cell type-specific DNA methylation patterns. This discovery defined a paradigm shift on the existing view on DNA methylation establishment offering a trailblazing perspective on the relationship between transcription and DNA methylation.

The main focus of Dr. Di Ruscio laboratory is to understand the impact of transcriptional activity in the establishment of epigenetic marks and to define the translational potential of RNAs as a tool to correct aberrant DNA methylation and other epigenetic marks (Ebralidze AK et al. preprint).
As aberrant DNA methylation is one of the most common molecular lesions in cancer cells, Di Ruscio’s group investigates the functional role of DiRs in myeloid disorders that are characterized by abnormal DNA methylation profile, such as Myelodysplastic Syndromes (MDS) and MDS evolution to Acute Myeloid Leukemia.
Using a pioneering approach, Di Ruscio’s group is developing DiR-mimicking platforms to correct DNA methylation profile globally and selectively in hematological and rare genetic conditions. The overarching goal of their studies is to generate RNA-guided gene-specific demethylating agents and overcome the toxicity and lack of specificity of currently approved hypomethylating therapies, with great benefit for patients’ quality of life and standard of cure  (Liu Y et al. preprint, Esposito, CL et al.).
More recently, Dr. Di Ruscio laboratory has started diving into understanding  the potential role of nicotinamide adenine dinucleotide (NAD) on DNA methylation and implication on normal and leukaemic  hematopoietic differentiation (Ummarino et al. 2021).

OUR PROJECTS

RNA-guided DNMT1 modulation

AGO2-mediated gene activation

AGO2-selective approach

Hematopoiesis & leukemia

Immune cell reprogramming

AptaDiR

Non-covalent and selective inhibition of DNMT1 may be achieved by aptamers. As a single-stranded DNA or RNA, an aptamer is the same type of molecule as the substrates for DNMT1, providing the possibility of competitive binding. Thus, an aptamer that can bind to a specific DNMT stronger than its native substrates, could inhibit its activity selectively via preventing the enzyme-substrate binding. Compared with the protein-based therapeutics, aptameric drugs are easier to be stored, handled, and modified to fit for medical applications; and can penetrate through biological barriers more easily, as well as possess much-reduced immunogenicity with low toxicity, presenting good promises for disease treatment. “Systematic Evolution of Ligands by EXponential enrichment” (SELEX) can help the discover of AptaDiR against DNMT1.

captaDiR

CaptaDiR is a next-generation RNA platform designed to achieve gene-specific DNA demethylation. Building upon the AptaDiR technology, CaptaDiR combines a DNMT1-interacting RNA domain with an additional sequence capable of recognizing a specific genomic target, generating a programmable chimeric RNA molecule. By coupling sequence recognition with selective epigenetic modulation, CaptaDiR is designed to enable targeted gene reactivation while preserving the native genomic architecture. This approach expands the versatility of RNA-based epigenetic therapeutics and provides a framework for precise regulation of disease-associated genes.

saRNA

Small activating RNAs (saRNAs) are double-stranded RNAs that increase the transcription of specific target genes. They function through an AGO2-dependent mechanism, whereby the RNA is loaded onto AGO2, transported into the nucleus, and directed to its genomic target to promote transcriptional activation. Our research focuses on a synthetic saRNA, AW1-51, targeting CEBPA, a key regulator of granulopoiesis, monopoiesis, lung development and liver function. Aberrant DNA methylation and reduced CEBPA expression have been associated with several diseases, including acute myeloid leukemia and lung cancer. Using leukemia and lung cancer models, we investigate whether AW1-51 promotes gene activation by acting as a DiR-mimicking molecule capable of reshaping the epigenetic landscape of the CEBPA locus and nearby regulatory elements.

DiR in blood

Myelodysplastic syndromes (MDS) are a collection of hematopoietic diseases characterized by ineffective hematopoiesis, cytopenia and risk of progression to acute myeloid leukemia (AML) in approximately 30 percent of the cases. MDS are considered the most common acquired bone marrow failure syndrome, primarily among the elderly – the median age at MDS diagnosis is ~70 years. Abnormal DNA methylation is considered the molecular lesion leading to tumor suppressor gene (TSG) silencing, MDS clonal variation, and a primary driver of disease evolution to AML. Since 2006, the FDA-approved hypomethylating agents (HMA) – Azacitidine, Decitabine, and Lenalidomide, have been the frontline therapies for the management of higher-risk to transform MDS, ineligible to more aggressive treatment, such as allogenic transplants and standard chemotherapy. Unfortunately, the high toxicity and global non-specific demethylation effects of these compounds have impaired their clinical application and limited their clinical indications. As the population continues to age (the percentage of people over 65 will double between 2025-2050), MDS incidence is expected to grow, and the development of non-toxic, more specific therapies is highly warranted.

The aim of this project is to link the presence or absence of DiRs  to global DNA methylation and gene expression in bone marrow mononuclear cells from patients with MDS and following evolution to AML and preclinical murine models of MDS-AML. By an integrated computational  analysis, we plan to identify molecular switches involved in leukemia development and capable of correcting abnormal DNA methylation.
In the long term, this study will lay the foundations of a transformative “personalized medicine” for targeted and precise correction of DNA methylation in MDS, leukemia, and all cancers caused by DNA methylation abnormalities with measurable improvement in patients’ life and standard of cure.

DiR in macrophage polarization

Macrophages are highly plastic immune cells that can adopt distinct functional states in response to environmental cues. The balance between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes plays a central role in tissue homeostasis, inflammation, and cancer. Our research investigates how epigenetic regulation, and in particular DNA methylation, contributes to macrophage polarization and functional plasticity. By developing RNA-based strategies to selectively modulate epigenetic pathways, we aim to better understand the molecular mechanisms controlling macrophage identity and explore new approaches for therapeutic immune modulation.

DiR in blood

Myelodysplastic syndromes (MDS) are a collection of hematopoietic diseases characterized by ineffective hematopoiesis, cytopenia and risk of progression to acute myeloid leukemia (AML) in approximately 30 percent of the cases. MDS are considered the most common acquired bone marrow failure syndrome, primarily among the elderly – the median age at MDS diagnosis is ~70 years. Abnormal DNA methylation is considered the molecular lesion leading to tumor suppressor gene (TSG) silencing, MDS clonal variation, and a primary driver of disease evolution to AML. Since 2006, the FDA-approved hypomethylating agents (HMA) – Azacitidine, Decitabine, and Lenalidomide, have been the frontline therapies for the management of higher-risk to transform MDS, ineligible to more aggressive treatment, such as allogenic transplants and standard chemotherapy. Unfortunately, the high toxicity and global non-specific demethylation effects of these compounds have impaired their clinical application and limited their clinical indications. As the population continues to age (the percentage of people over 65 will double between 2025-2050), MDS incidence is expected to grow, and the development of non-toxic, more specific therapies is highly warranted.

The aim of this project is to link the presence or absence of DiRs  to global DNA methylation and gene expression in bone marrow mononuclear cells from patients with MDS and following evolution to AML and preclinical murine models of MDS-AML. By an integrated computational  analysis, we plan to identify molecular switches involved in leukemia development and capable of correcting abnormal DNA methylation.
In the long term, this study will lay the foundations of a transformative “personalized medicine” for targeted and precise correction of DNA methylation in MDS, leukemia, and all cancers caused by DNA methylation abnormalities with measurable improvement in patients’ life and standard of cure.

DiR in macrophage polarization

Macrophages are highly plastic immune cells that can adopt distinct functional states in response to environmental cues. The balance between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes plays a central role in tissue homeostasis, inflammation, and cancer. Our research investigates how epigenetic regulation, and in particular DNA methylation, contributes to macrophage polarization and functional plasticity. By developing RNA-based strategies to selectively modulate epigenetic pathways, we aim to better understand the molecular mechanisms controlling macrophage identity and explore new approaches for therapeutic immune modulation.

PEOPLE

INSIDERS

Annalisa Di Ruscio

Annalisa Di Ruscio

Principal Investigator, MD, PhD
“ὁ δὲ ἀνεξέταστος βίος οὐ βιωτὸς ἀνθρώπῳ” “the unexamined life is not worth living” - Plato
Juan Rodrigo Patiño Mercau

Juan Rodrigo Patiño Mercau

Post-Doc Research Fellow, PhD
In life you can let yourself go, or you can decide more about the situations around you. Everyone chooses his or her attitude
Davide D’Onghia

Davide D’Onghia

Post-Doc Research Fellow, PhD
"καλὸς καὶ ἀγαθός" "Noble and virtuous"
Kavya Alagendran

Kavya Alagendran

MS
The key of persistence opens all doors closed by resistence
Alexus Phommachanh

Alexus Phommachanh

MS Student

Jackson Ellis

MS Student

Isabella Viscovich

MS Student

OUTSIDERS

Simone Ummarino

Simone Ummarino

Post-Doc Research Fellow, PhD
Harvard Stem Cell Institute, Harvard Medical School, Boston, USA; Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA
Laura Seclì

Laura Seclì

Web Designer, Scientific Illustrator, PhD
Believing in the potentiality of art to efficiently communicate science

COLLABORATORS

Carla Esposito

Carla Esposito

Permanent Scientist
Institute Experimental Endocrinology and Oncology (IEOS), CNR, Milan, Italy
Vittorio de Franciscis

Vittorio de Franciscis

Senior Collaborator CNR
Institute of Genetic and Biomedical Research (IRGB), CNR, Milan, Italy
Marcin Kortylewski

Marcin Kortylewski

Professor
Institute of Genetic and Biomedical Research (IRGB), CNR, Milan, Italy
Ida Autiero

Ida Autiero

Permanent Scientist
Institute of Biostructures and Bioimaging, IBB-CNR, Naples, Italy
Annamaria Sandomenico

Annamaria Sandomenico

Permanent Scientist
Institute of Biostructures and Bioimaging, IBB-CNR, Naples, Italy
Menotti Ruvo

Menotti Ruvo

Permanent Scientist
Institute of Biostructures and Bioimaging, IBB-CNR, Naples, Italy
Daniel G Tenen

Daniel G Tenen

Professor of Medicine
Harvard Stem Cell Institute, Harvard Medical School, Boston, USA; Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA; Cancer Science Institute of Singapore, National University of Singapore, Singapore
Alexander Ebralidze

Alexander Ebralidze

Principal Research Associate
Harvard Stem Cell Institute, Harvard Medical School, Boston, USA; Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA
Mahmoud A Bassal

Mahmoud A Bassal

Bioinformatician, Instructor
Harvard Stem Cell Institute, Harvard Medical School, Boston, USA; Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA; Cancer Science Institute of Singapore, National University of Singapore, Singapore
Giulia Gaggi

Giulia Gaggi

Visiting Post-Doc Research Fellow, PhD
“Everything is theoretically impossible, until it is done” - Robert A. Heinlein
Elisabetta Tabolacci

Elisabetta Tabolacci

Principal Investigator, MD
Sezione di Medicina Genomica, Dipartimento Universitario Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Veronica Nobile

Veronica Nobile

Post-Doc Research Fellow, PhD
Sezione di Medicina Genomica, Dipartimento Universitario Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Barbara (Basia) Wegiel

Barbara (Basia) Wegiel

Principal Investigator, PhD, DSc
Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
Barbara Ghinassi

Barbara Ghinassi

Professor of Human Anatomy, PhD
Reprogramming and Cell Differentiation Lab, Center for Advanced Studies and Technology (CAST) Department of Medicine and Aging Sciences University “G. d’Annunzio” Chieti-Pescara, Italy
Khush Joshi

Khush Joshi

AI Research Scientist
Harvard Medical School, Boston, USA

ALUMNI

Umberto Cinotti

Soomin (Christine) Cho

Aiden Engel

Olivia Kohn

Yanjing Liu

Vivian Liu

Orlaith McDonagh

Giulia Poppo

Lucrezia Rinaldi

Kealy Santos

Austin Wei

LAB FUN

Lab Picture 1
MORE

PEOPLE

INSIDERS

Annalisa Di Ruscio

Annalisa Di Ruscio

Principal Investigator, MD, PhD
“ὁ δὲ ἀνεξέταστος βίος οὐ βιωτὸς ἀνθρώπῳ” “the unexamined life is not worth living” - Plato
Juan Rodrigo Patiño Mercau

Juan Rodrigo Patiño Mercau

Post-Doc Research Fellow, PhD
In life you can let yourself go, or you can decide more about the situations around you. Everyone chooses his or her attitude
Davide D’Onghia

Davide D’Onghia

Post-Doc Research Fellow, PhD
"καλὸς καὶ ἀγαθός" "Noble and virtuous"
Kavya Alagendran

Kavya Alagendran

MS
The key of persistence opens all doors closed by resistence
Alexus Phommachanh

Alexus Phommachanh

MS Student

Jackson Ellis

MS Student

Isabella Viscovich

MS Student

OUTSIDERS

Simone Ummarino

Simone Ummarino

Post-Doc Research Fellow, PhD
Harvard Stem Cell Institute, Harvard Medical School, Boston, USA; Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA
Laura Seclì

Laura Seclì

Web Designer, Scientific Illustrator, PhD
Believing in the potentiality of art to efficiently communicate science

COLLABORATORS

Carla Esposito

Carla Esposito

Permanent Scientist
Institute Experimental Endocrinology and Oncology (IEOS), CNR, Milan, Italy
Vittorio de Franciscis

Vittorio de Franciscis

Senior Collaborator CNR
Institute of Genetic and Biomedical Research (IRGB), CNR, Milan, Italy
Marcin Kortylewski

Marcin Kortylewski

Professor
Institute of Genetic and Biomedical Research (IRGB), CNR, Milan, Italy
Ida Autiero

Ida Autiero

Permanent Scientist
Institute of Biostructures and Bioimaging, IBB-CNR, Naples, Italy
Annamaria Sandomenico

Annamaria Sandomenico

Permanent Scientist
Institute of Biostructures and Bioimaging, IBB-CNR, Naples, Italy
Menotti Ruvo

Menotti Ruvo

Permanent Scientist
Institute of Biostructures and Bioimaging, IBB-CNR, Naples, Italy
Daniel G Tenen

Daniel G Tenen

Professor of Medicine
Harvard Stem Cell Institute, Harvard Medical School, Boston, USA; Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA; Cancer Science Institute of Singapore, National University of Singapore, Singapore
Alexander Ebralidze

Alexander Ebralidze

Principal Research Associate
Harvard Stem Cell Institute, Harvard Medical School, Boston, USA; Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA
Mahmoud A Bassal

Mahmoud A Bassal

Bioinformatician, Instructor
Harvard Stem Cell Institute, Harvard Medical School, Boston, USA; Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA; Cancer Science Institute of Singapore, National University of Singapore, Singapore
Giulia Gaggi

Giulia Gaggi

Visiting Post-Doc Research Fellow, PhD
“Everything is theoretically impossible, until it is done” - Robert A. Heinlein
Elisabetta Tabolacci

Elisabetta Tabolacci

Principal Investigator, MD
Sezione di Medicina Genomica, Dipartimento Universitario Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Veronica Nobile

Veronica Nobile

Post-Doc Research Fellow, PhD
Sezione di Medicina Genomica, Dipartimento Universitario Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Barbara (Basia) Wegiel

Barbara (Basia) Wegiel

Principal Investigator, PhD, DSc
Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
Barbara Ghinassi

Barbara Ghinassi

Professor of Human Anatomy, PhD
Reprogramming and Cell Differentiation Lab, Center for Advanced Studies and Technology (CAST) Department of Medicine and Aging Sciences University “G. d’Annunzio” Chieti-Pescara, Italy
Khush Joshi

Khush Joshi

AI Research Scientist
Harvard Medical School, Boston, USA

ALUMNI

Umberto Cinotti

Soomin (Christine) Cho

Aiden Engel

Olivia Kohn

Yanjing Liu

Vivian Liu

Orlaith McDonagh

Giulia Poppo

Lucrezia Rinaldi

Kealy Santos

Austin Wei

LAB FUN

Lab Picture 1
MORE

LAB RESOURCES

SELECTED PUBLICATIONS

SEE HERE

Ummarino S, Poluben L, Ebralidze AK, Autiero I, Rinaldi L, Paniza T, Deshpande M, Mandel NH, Lee JD, Zhang Y, Bassal MA, Budnik B, Trinh BQ, Balk SP, Flaumenhaft R, Gerhardt J, Mirkin SM, Tenen DG, Di Ruscio A. RNAs anchoring replication complex control initiation and firing of DNA replication. Nat Commun. 2026 May 27. doi: 10.1038/s41467-026-73478-2. Epub ahead of print. PMID: 42203769.

Wang D, Kaniowski D, Jacek K, Su YL, Yu C, Hall J, Li H, Feng M, Hui S, Kaminska B, De Franciscis V, Esposito CL, Di Ruscio A, Zhang B, Marcucci G, Kuo YH, Kortylewski M. Bi-functional CpG-STAT3 decoy oligonucleotide triggers multilineage differentiation of acute myeloid leukemia in mice. Mol Ther Nucleic Acids. 2024 Sep 10;35(3):102268. doi: 10.1016/j.omtn.2024.102268. eCollection 2024 Sep 10. PubMed PMID: 39171140; PubMed Central PMCID: PMC11338104.

 

Esposito CL, Autiero I, Sandomenico A, Li H, Bassal MA, Ibba ML, Wang D, Rinaldi L, Ummarino S, Gaggi G, Borchiellini M, Swiderski P, Ruvo M, Catuogno S, Ebralidze AK, Kortylewski M, de Franciscis V, Di Ruscio A. Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation. Nat Commun. 2023 Jan 6

Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J, Figueroa ME, De Figueiredo Pontes LL, Alberich-Jorda M, Zhang P, Wu M, D’Alò F, Melnick A, Leone G, Ebralidze KK, Pradhan S, Rinn JL, Tenen DG. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature. 2013 Nov 21

Amabile G, Di Ruscio A, Müller F, Welner RS, Yang H, Ebralidze AK, Zhang H, Levantini E, Qi L, Martinelli G, Brummelkamp T, Le Beau MM, Figueroa ME, Bock C, Tenen DG. Dissecting the role of aberrant DNA methylation in human leukaemia. Nat Commun. 2015 May 22

Tan HK, Wu CS, Li J, Tan ZH, Hoffman JR, Fry CJ, Yang H, Di Ruscio A, Tenen DG. DNMT3B shapes the mCA landscape and regulates mCG for promoter bivalency in human embryonic stem cells. Nucleic Acids Res. 2019 Aug 22

Ummarino S, Hausman C, Gaggi G, Rinaldi L, Bassal MA, Zhang Y, Seelam AJ, Kobayashi IS, Borchiellini M, Ebralidze AK, Ghinassi B, Trinh BQ, Kobayashi SS, Di Ruscio A. NAD Modulates DNA Methylation and Cell Differentiation. Cells. 2021 Nov 2

Trinh BQ, Ummarino S, Zhang Y, Ebralidze AK, Bassal MA, Nguyen TM, Heller G, Coffey R, Tenen DE, van der Kouwe E, Fabiani E, Gurnari C, Wu CS, Angarica VE, Yang H, Chen S, Zhang H, Thurm AR, Marchi F, Levantini E, Staber PB, Zhang P, Voso MT, Pandolfi PP, Kobayashi SS, Chai L, Di Ruscio A, Tenen DG. Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML. Blood. 2021 Oct 14

 

Preprints

Gaggi G, Patiño-Mercau JR, Borchiellini M, Li M, Rinaldi L, Maroni G, D’Onghia D, Kobayashi SS, Bassal MA, Habib NA, Medina PP, Di Baldassarre A, Ghinassi B, Ebralidze AK, Ummarino S, Tenen DG, Di Ruscio A. Small activating RNA AW1-51 (CEBPA-51) elicits targeted DNA demethylation to promote gene activation. bioRxiv [Preprint]. 2025 Sep 30:2025.09.29.679274. doi: 10.1101/2025.09.29.679274. PMID: 41256513; PMCID: PMC12621981.

Targeted intragenic demethylation initiates chromatin rewiring for gene activation. Yanjing V. Liu, Mahmoud A. Bassal, Migara Kavishka Jayasinghe, Quy Xiao Xuan Lin, Chan-Shuo Wu, Jing Ping Tang, Junsu Kwon, Qiling Zhou, Hong Kee Tan, Alexander K.Ebralidze, Minh T.N. Le, Li Chai, Touati Benoukraf, Annalisa Di Ruscio, Daniel G.Tenen. bioRxiv 2020.07.16

 
Formation and recycling of an active epigenetic mark mediated by cell cycle-specific RNAs. Alexander K.Ebralidze, Simone Ummarino, Mahmoud A.Bassal, Haoran Zhang, Bogdan Budnik, Emanuele Monteleone, Dennis Kappei, Yanjing V.Liu, Danielle E.Tenen, Rory Coffey, Mee Rie Sheen, Yanzhou Zhang, Anaïs Wanet, Bon Q. Trinh, Valeria Poli, Vladimir Espinosa Angarica, Roberto Tirado Magallanes, Touati Benoukraf, Coly nCrane-Robinson, Annalisa Di  Ruscio, Daniel G. Tenen. bioRxiv 2021.10.27.466094.

FUNDING

NEWS AND VIEWS

August 24, 2026

New paper from the Di Ruscio Lab! We are excited to share our latest work, now published in Nature Communications…

August 7, 2026

Before heading off for a well-deserved summer break, the Di Ruscio Lab gathered for our annual summer dinner. It was…

August 6, 2026

Thank you, Vivian! We were delighted to host Vivian Liu as an HSCI Summer Intern in the Di Ruscio Lab…

December 20, 2025

Congratulations to Juan Rodrigo Patiño Mercau on his excellent presentation at MIT on December 4. We are so proud!

December 20, 2025

We had a wonderful time at our Yankee holiday exchange! Happy Holidays to all!

December 18, 2025

Happy holidays from the Di Ruscio lab

CONTACT

  • Beth Israel Deaconess Medical Center,
    Center for Life Science, Room CLS 407,
    3 Blackfan Circle,
    Boston, MA, 02115
  • 617-735-2022
  • 617-735-2222
  • adirusci@bidmc.harvard.edu
  • okohn@bidmc.harvard.edu
  • Contact form

LAB RESOURCES

SELECTED PUBLICATIONS

SEE HERE

Ummarino S, Poluben L, Ebralidze AK, Autiero I, Rinaldi L, Paniza T, Deshpande M, Mandel NH, Lee JD, Zhang Y, Bassal MA, Budnik B, Trinh BQ, Balk SP, Flaumenhaft R, Gerhardt J, Mirkin SM, Tenen DG, Di Ruscio A. RNAs anchoring replication complex control initiation and firing of DNA replication. Nat Commun. 2026 May 27. doi: 10.1038/s41467-026-73478-2. Epub ahead of print. PMID: 42203769.

Wang D, Kaniowski D, Jacek K, Su YL, Yu C, Hall J, Li H, Feng M, Hui S, Kaminska B, De Franciscis V, Esposito CL, Di Ruscio A, Zhang B, Marcucci G, Kuo YH, Kortylewski M. Bi-functional CpG-STAT3 decoy oligonucleotide triggers multilineage differentiation of acute myeloid leukemia in mice. Mol Ther Nucleic Acids. 2024 Sep 10;35(3):102268. doi: 10.1016/j.omtn.2024.102268. eCollection 2024 Sep 10. PubMed PMID: 39171140; PubMed Central PMCID: PMC11338104.

 

Esposito CL, Autiero I, Sandomenico A, Li H, Bassal MA, Ibba ML, Wang D, Rinaldi L, Ummarino S, Gaggi G, Borchiellini M, Swiderski P, Ruvo M, Catuogno S, Ebralidze AK, Kortylewski M, de Franciscis V, Di Ruscio A. Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation. Nat Commun. 2023 Jan 6

Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J, Figueroa ME, De Figueiredo Pontes LL, Alberich-Jorda M, Zhang P, Wu M, D’Alò F, Melnick A, Leone G, Ebralidze KK, Pradhan S, Rinn JL, Tenen DG. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature. 2013 Nov 21

Amabile G, Di Ruscio A, Müller F, Welner RS, Yang H, Ebralidze AK, Zhang H, Levantini E, Qi L, Martinelli G, Brummelkamp T, Le Beau MM, Figueroa ME, Bock C, Tenen DG. Dissecting the role of aberrant DNA methylation in human leukaemia. Nat Commun. 2015 May 22

Tan HK, Wu CS, Li J, Tan ZH, Hoffman JR, Fry CJ, Yang H, Di Ruscio A, Tenen DG. DNMT3B shapes the mCA landscape and regulates mCG for promoter bivalency in human embryonic stem cells. Nucleic Acids Res. 2019 Aug 22

Ummarino S, Hausman C, Gaggi G, Rinaldi L, Bassal MA, Zhang Y, Seelam AJ, Kobayashi IS, Borchiellini M, Ebralidze AK, Ghinassi B, Trinh BQ, Kobayashi SS, Di Ruscio A. NAD Modulates DNA Methylation and Cell Differentiation. Cells. 2021 Nov 2

Trinh BQ, Ummarino S, Zhang Y, Ebralidze AK, Bassal MA, Nguyen TM, Heller G, Coffey R, Tenen DE, van der Kouwe E, Fabiani E, Gurnari C, Wu CS, Angarica VE, Yang H, Chen S, Zhang H, Thurm AR, Marchi F, Levantini E, Staber PB, Zhang P, Voso MT, Pandolfi PP, Kobayashi SS, Chai L, Di Ruscio A, Tenen DG. Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML. Blood. 2021 Oct 14

 

Preprints

Gaggi G, Patiño-Mercau JR, Borchiellini M, Li M, Rinaldi L, Maroni G, D’Onghia D, Kobayashi SS, Bassal MA, Habib NA, Medina PP, Di Baldassarre A, Ghinassi B, Ebralidze AK, Ummarino S, Tenen DG, Di Ruscio A. Small activating RNA AW1-51 (CEBPA-51) elicits targeted DNA demethylation to promote gene activation. bioRxiv [Preprint]. 2025 Sep 30:2025.09.29.679274. doi: 10.1101/2025.09.29.679274. PMID: 41256513; PMCID: PMC12621981.

Targeted intragenic demethylation initiates chromatin rewiring for gene activation. Yanjing V. Liu, Mahmoud A. Bassal, Migara Kavishka Jayasinghe, Quy Xiao Xuan Lin, Chan-Shuo Wu, Jing Ping Tang, Junsu Kwon, Qiling Zhou, Hong Kee Tan, Alexander K.Ebralidze, Minh T.N. Le, Li Chai, Touati Benoukraf, Annalisa Di Ruscio, Daniel G.Tenen. bioRxiv 2020.07.16

 
Formation and recycling of an active epigenetic mark mediated by cell cycle-specific RNAs. Alexander K.Ebralidze, Simone Ummarino, Mahmoud A.Bassal, Haoran Zhang, Bogdan Budnik, Emanuele Monteleone, Dennis Kappei, Yanjing V.Liu, Danielle E.Tenen, Rory Coffey, Mee Rie Sheen, Yanzhou Zhang, Anaïs Wanet, Bon Q. Trinh, Valeria Poli, Vladimir Espinosa Angarica, Roberto Tirado Magallanes, Touati Benoukraf, Coly nCrane-Robinson, Annalisa Di  Ruscio, Daniel G. Tenen. bioRxiv 2021.10.27.466094.

FUNDING

NEWS AND VIEWS

August 24, 2026

New paper from the Di Ruscio Lab! We are excited to share our latest work, now published in Nature Communications…

August 7, 2026

Before heading off for a well-deserved summer break, the Di Ruscio Lab gathered for our annual summer dinner. It was…

CONTACT

  • Beth Israel Deaconess Medical Center,
    Center for Life Science, Room CLS 407,
    3 Blackfan Circle,
    Boston, MA, 02115
  • 617-735-2022
  • 617-735-2222
  • adirusci@bidmc.harvard.edu
  • okohn@bidmc.harvard.edu
  • Contact form