About

Danesh Moazed is associated with Harvard's Department of Molecular & Cellular Biology and has been involved in the administration and mentorship of the Biochemical Sciences Tutorial Program since 2017. His role involves pairing students with faculty tutors to facilitate discussions on research papers, scientific ideas, and career paths, emphasizing learning through primary literature reading in a low-stakes environment. Moazed's contributions support the program's goal of fostering scientific thinking, professional relationships, and mentorship, which are central to Harvard’s tutorial model. His work helps maintain the tradition of close engagement with scientific research and mentorship that has been a hallmark of Harvard’s undergraduate life sciences education for nearly a century.

Research topics

• Genetics
• Biology

Selected publications

• Genetic compensation in β-actin mutants occurs independently of mutations that destabilize β-actin mRNA

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-24

  articleOpen accessSenior authorCorresponding

  Abstract Proper maintenance of gene expression in response to mutations or environmental fluctuations is critical for cell development and survival. Recently, a novel genetic compensation mechanism was described wherein mutant mRNA decay triggers increased transcription of paralogous genes. This effect was reported for several genes, including β-actin ( Actb ) in mouse embryonic stem cells, where Actb mRNA with a premature termination codon enhances transcription of its paralog, γ-actin ( Actg1 ), and partially rescues cytoskeletal defects. Here we show that, in both mouse and human embryonic stem cells, mutations in the ACTB gene, regardless of mutant mRNA expression, trigger genetic compensation. Furthermore, transgenic expression of mutant ACTB mRNA with a premature stop codon fails to induce genetic compensation. Depletion of the SRF or MRTF-A transcription factors, which are known to increase ACTB transcription in response to low ACTB protein levels, diminishes the genetic compensation response in ACTB mutants. These results suggest that genetic compensation in ACTB mutants is primarily mediated by a transcriptional feedback loop via SRF/MRTF-A, independent of the expression or degradation of mutant ACTB mRNA.

  PublisherDOI

• Epigenetic Inheritance Through Replication-Coupled Parental Histone Recycling

  Annual Review of Cell and Developmental Biology · 2026-04-20

  articleSenior author

  Epigenetic inheritance of repressed chromatin domains plays a central role in the stable silencing of cell type-specific genes and transposons in eukaryotes. Silent chromatin domains are associated with repressive histone modifications, and their propagation requires a read-write mechanism involving recognition of histone modifications by enzymes that also catalyze them. The recycling of parental histones during DNA replication plays a crucial role in maintaining chromatin states by providing the substrate for read-write enzymes. Here we describe recent advances in understanding how the DNA replication machinery and its associated histone chaperones mediate symmetrical parental histone transfer to newly replicated daughter DNA strands and evidence that this process is required for the epigenetic inheritance of silent chromatin domains.

  PublisherDOI

• Requirements for establishment and epigenetic stability of mammalian heterochromatin

  Molecular Cell · 2025-09-01 · 6 citations

  articleOpen accessSenior author

  Heterochromatic domains of DNA account for a large fraction of mammalian genomes and play critical roles in silencing transposons and genes, but the mechanisms that establish and maintain these domains are not fully understood. Here, we use a CRISPR-based genetic screen to investigate the requirements for establishment and maintenance of histone H3 lysine 9 trimethylation (H3K9me3) heterochromatin. In mouse embryonic stem cells (mESCs), we show that transiently induced H3K9me3 heterochromatin is inherited for a limited number of cell divisions, independently of sequence-dependent recruitment, but becomes stable upon differentiation, concomitant with downregulation of enzymes erasing H3K9me and DNA methylation. In addition, ordered and non-redundant activities of multiple H3K9 and DNA methyltransferases, together with histone deacetylases, chromatin remodeling complexes, and RNA processing factors, are required for heterochromatin maintenance. Our findings suggest that a newly acquired H3K9me3 domain can be maintained like an imprint but requires reinforcement by DNA methylation and other pathways.

  PublisherOA PDFDOI

• Catalytic pocket of Clr4 (Suv39h) methyltransferase serves as a substrate receptor for Cullin 4-dependent histone H3 ubiquitination

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-30

  preprintOpen accessSenior authorCorresponding

  Histone H3 lysine 9 (H3K9) methylation must be regulated to prevent inappropriate heterochromatin formation. Regulation of the conserved fission yeast H3K9 methyltransferase Clr4 (Suv39h) involves an automethylation-induced conformational switch and interaction of its catalytic SET domain with mono-ubiquitinated histone H3 lysine 14 (H3K14ub), a modification catalyzed by the Cul4 subunit of the CLRC complex. Using reconstituted CLRC, we show that Clr4 catalytic pocket serves as a substrate receptor for Cul4-dependent H3K14 ubiquitination. H3K14ub activates Clr4 to catalyze cis methylation of H3K9 on the same histone tail, while Clr4 automethylation enables H3K14ub-bound Clr4 to methylate H3K9 on an unmodified H3 tail in trans. Crosslinking and structural modeling reveal interactions between Clr4 chromo and SET domains, and between the chromodomain and H3K14ub, suggesting that the chromodomain reads H3K9me3 and H3K14ub to allosterically regulate Clr4 activity. H3K14 ubiquitination therefore regulates Clr4 by promoting its recruitment and by positioning H3K9 in the active site.

  PublisherOA PDFDOI

• Raw ND2 confocal z-stacks associated with the manuscript: "Genetic compensation in β-actin mutants occurs independently of mutations that destabilize β-actin mRNA"

  Zenodo (CERN European Organization for Nuclear Research) · 2024-04-22

  datasetOpen accessSenior author

  Raw ND2 confocal z-stacks associated with the manuscript:"Genetic compensation in β-actin mutants occurs independently of mutations that destabilize β-actin mRNA" Moazed Lab, Harvard Medical School. Authors: Authors: Harleen Saini(1), Jiuchun Zhang(2), Hiba Dardari(1†), Danesh Moazed(1*)Affiliations: (1) Howard Hughes Medical Institute, Department of Cell Biology, Blavatnik Institute, Harvard Medical School; Boston, MA, USA. (2) Department of Cell Biology, Blavatnik Institute, Harvard Medical School; Boston, MA, USA. (†) Present address: Lewis-Sigler Institute for Integrative Genomics, Princeton University; Princeton, NJ, USA.(*) Corresponding author. Email: danesh@hms.harvard.edu Contents:hESC F-actin/G-actin quantification images (phalloidin + DNase I staining)Genotypes: Wild-type (wt), ACTB-∆4nt (heterozygous ACTB 4-nucleotide deletion in the coding sequence, del4nt), ACTB-∆gene (heterozygous ACTB gene deletion, delgene). Analysis code available at: https://github.com/harleensaini/MoazedLab_hESC-actin-quantification Preprint available at: https://doi.org/10.64898/2026.04.21.719943

  PublisherDOI

• Raw ND2 confocal z-stacks associated with the manuscript: "Genetic compensation in β-actin mutants occurs independently of mutations that destabilize β-actin mRNA"

  Zenodo (CERN European Organization for Nuclear Research) · 2024-04-22

  datasetOpen accessSenior author

  Raw ND2 confocal z-stacks associated with the manuscript:"Genetic compensation in β-actin mutants occurs independently of mutations that destabilize β-actin mRNA" Moazed Lab, Harvard Medical School. Authors: Authors: Harleen Saini(1), Jiuchun Zhang(2), Hiba Dardari(1†), Danesh Moazed(1*)Affiliations: (1) Howard Hughes Medical Institute, Department of Cell Biology, Blavatnik Institute, Harvard Medical School; Boston, MA, USA. (2) Department of Cell Biology, Blavatnik Institute, Harvard Medical School; Boston, MA, USA. (†) Present address: Lewis-Sigler Institute for Integrative Genomics, Princeton University; Princeton, NJ, USA.(*) Corresponding author. Email: danesh@hms.harvard.edu Contents:hESC F-actin/G-actin quantification images (phalloidin + DNase I staining)Genotypes: Wild-type (wt), ACTB-∆4nt (heterozygous ACTB 4-nucleotide deletion in the coding sequence, del4nt), ACTB-∆gene (heterozygous ACTB gene deletion, delgene). Analysis code available at: https://github.com/harleensaini/MoazedLab_hESC-actin-quantification Preprint available at: https://doi.org/10.64898/2026.04.21.719943

  PublisherDOI

• A replisome-associated histone H3-H4 chaperone required for epigenetic inheritance

  Cell · 2024-08-01 · 47 citations

  articleOpen accessSenior author

  Faithful transfer of parental histones to newly replicated daughter DNA strands is critical for inheritance of epigenetic states. Although replication proteins that facilitate parental histone transfer have been identified, how intact histone H3-H4 tetramers travel from the front to the back of the replication fork remains unknown. Here, we use AlphaFold-Multimer structural predictions combined with biochemical and genetic approaches to identify the Mrc1/CLASPIN subunit of the replisome as a histone chaperone. Mrc1 contains a conserved histone-binding domain that forms a brace around the H3-H4 tetramer mimicking nucleosomal DNA and H2A-H2B histones, is required for heterochromatin inheritance, and promotes parental histone recycling during replication. We further identify binding sites for the FACT histone chaperone in Swi1/TIMELESS and DNA polymerase α that are required for heterochromatin inheritance. We propose that Mrc1, in concert with FACT acting as a mobile co-chaperone, coordinates the distribution of parental histones to newly replicated DNA.

  PublisherDOI

• Minimal requirements for the epigenetic inheritance of engineered silent chromatin domains

  Proceedings of the National Academy of Sciences · 2024-01-10 · 6 citations

  articleOpen accessSenior authorCorresponding

  Mechanisms enabling genetically identical cells to differentially regulate gene expression are complex and central to organismal development and evolution. While gene silencing pathways involving DNA sequence–specific recruitment of histone-modifying enzymes are prevalent in nature, examples of sequence-independent heritable gene silencing are scarce. Studies of the fission yeast Schizosaccharomyces pombe indicate that sequence-independent propagation of heterochromatin can occur but requires numerous multisubunit protein complexes and their diverse activities. Such complexity has so far precluded a coherent articulation of the minimal requirements for heritable gene silencing by conventional in vitro reconstitution approaches. Here, we take an unconventional approach to defining these requirements by engineering sequence-independent silent chromatin inheritance in budding yeast Saccharomyces cerevisiae cells. The mechanism conferring memory upon these cells is remarkably simple and requires only two proteins, one that recognizes histone H3 lysine 9 methylation (H3K9me) and catalyzes the deacetylation of histone H4 lysine 16 (H4K16), and another that recognizes deacetylated H4K16 and catalyzes H3K9me. Together, these bilingual “read–write” proteins form an interdependent positive feedback loop that is sufficient for the transmission of DNA sequence–independent silent information over multiple generations.

  PublisherOA PDFDOI

• Genomic context– and H2AK119 ubiquitination–dependent inheritance of human Polycomb silencing

  Science Advances · 2024-05-08 · 9 citations

  articleOpen accessSenior authorCorresponding

  Polycomb repressive complexes 1 and 2 (PRC1 and 2) are required for heritable repression of developmental genes. The cis- and trans-acting factors that contribute to epigenetic inheritance of mammalian Polycomb repression are not fully understood. Here, we show that, in human cells, ectopically induced Polycomb silencing at initially active developmental genes, but not near ubiquitously expressed housekeeping genes, is inherited for many cell divisions. Unexpectedly, silencing is heritable in cells with mutations in the H3K27me3 binding pocket of the Embryonic Ectoderm Development (EED) subunit of PRC2, which are known to disrupt H3K27me3 recognition and lead to loss of H3K27me3. This mode of inheritance is less stable and requires intact PRC2 and recognition of H2AK119ub1 by PRC1. Our findings suggest that maintenance of Polycomb silencing is sensitive to local genomic context and can be mediated by PRC1-dependent H2AK119ub1 and PRC2 independently of H3K27me3 recognition.

  PublisherOA PDFDOI

• Contributors

  Elsevier eBooks · 2023-09-29

  book-chapter
  PublisherDOI

Recent grants

• NIH Grant R01GM061641

  NIH · $3.9M · 2016

• NIH Grant R01GM079535

  NIH · $1.0M · 2012

• Epigenetic inheritance of heterochromatin

  NIH · $6.6M · 2005–2026

Frequent coauthors

• Steven P. Gygi

  62 shared

• Nahid Iglesias

  Duke University

  39 shared

• Shiv I. S. Grewal

  National Institutes of Health

  29 shared

• André Verdel

  Inserm

  26 shared

• Harry F. Noller

  University of California, Santa Cruz

  25 shared

• Gloria Jih

  Century Therapeutics (United States)

  24 shared

• Haining Zhou

  Howard Hughes Medical Institute

  24 shared

• Mark A. Currie

  University of Toronto

  22 shared

Labs

• Harvard’s Biochemical Sciences Tutorial ProgramPI