About

Most heritable information is encoded in DNA. Turning the information encoded in DNA into real-life biological actions such as cell division, growth of an embryo, or sensation of the environment requires an extensive system of interdependent proteins and RNA, called chromatin. Chromatin interacts with the DNA strands and ‘remembers’ what a particular cell is doing across long periods of time and even across generations, a phenomenon known as epigenetic memory. We apply both experimental and computational approaches to understand how epigenetic memory works, and how it affects development of individuals and evolution of species.

Research topics

• Biology
• Genetics
• Cell biology

Selected publications

• Fertilization with Protamine-2 deficient sperm triggers abnormal pronucleus development and zygotic cleavage

  Biology of Reproduction · 2026-01-18

  articleOpen access

  Spermatozoan DNA is hyper-condensed by protamines, which are essential for sperm motility and function. Since defects in this process impact natural fertilization, little is known about how changes to protamine-mediated condensation impact the oocyte's ability to recognize and reprogram the paternal genetic material for the early stages of embryogenesis. Here, we performed intracytoplasmic sperm injection (ICSI) with sperm lacking Protamine 2 (Prm2 KO) and tracked preimplantation development in mice. We found that ICSI with Prm2 KO sperm leads to embryo fragmentation and arrest at the 2-cell stage. Surprisingly, injected Prm2 KO sperm DNA is rapidly depleted from the oocyte during the completion of maternal meiosis II, leading to a zygote with one morphologically abnormal pronucleus. Direct induction of DNA damage in wild type sperm did not recapitulate the pronuclear abnormalities found in Prm2 KO-derived zygotes. Co-injection with wild type sperm failed to rescue these defects, indicating that they were not caused by absence of a normally protaminated paternal genome. Finally, we find that testicular Prm2 KO sperm support progression to the blastocyst stage, suggesting a model where fertility-compromising factors are acquired during epididymal maturation. Our results demonstrate that Protamine 2 is necessary for correct maturation of epididymal sperm and essential for their ability to form a functional zygote at fertilization.

  PublisherOA PDFDOI

• Ancestral chromatin state constrains the functional landscape of bivalent domains in mammalian spermatogenesis

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-16

  articleOpen accessSenior authorCorresponding

  Mammalian germ cells are enriched for bivalent chromatin, an epigenetic state defined by the dual presence of the activating H3K4me3 and repressive H3K27me3 histone modifications. Bivalency is evolutionarily conserved at developmentally important genes in germ cells but diverges at hundreds of additional loci, and evolutionary gains in bivalency have been proposed to reflect divergent somatic functions of the associated genes. Here, we sought to discover if evolutionary gains in bivalency occur selectively at genes with specific functions, and to better elucidate the role of bivalent chromatin in germ cells. By comparing genome-wide profiles for four histone modifications in spermatogenic cells of six mammalian species, we define a comprehensive set of mammalian bivalent domains and classify them based on conservation or divergence of chromatin state. We find that evolutionarily conserved bivalent regions exhibit canonical features of bivalency and maintain bivalency in embryonic stem cells. In contrast, bivalent domains emerging from a purely active or repressed ancestral chromatin state have atypical sequence and regulatory features and are frequently germ cell specific. Genes associated with these recent bivalent domains exhibit distinct somatic expression patterns that reflect their ancestral chromatin state in germ cells. Specifically, bivalent genes emerging from ancestrally active chromatin are more highly expressed in somatic tissues and are enriched for immune-related functions, while those emerging from ancestrally H3K27me3-only domains are lowly expressed in the soma and enriched for neurogenesis functions. We propose that recent bivalent regions demarcate sites of regulatory sequence change that preferentially impacts specific somatic lineages.

  PublisherOA PDFDOI

• 3D chromatin compartment of round spermatids encodes the spatiotemporal program of histone-to-protamine exchange in spermiogenesis

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-12

  articleOpen access

  Sperm formation requires a radical chromatin reorganization, where nucleosomes are replaced by transition proteins (TNPs) and subsequently by protamines (PRM1 and PRM2). Although essential for fertility, the regulatory logic governing this exchange is unknown, but it's presumed to be stochastic and unregulated. Using endogenously tagged PRM mouse models and stage-resolved, genome-wide profiling, we revise the order of histone-to-protamine exchange and show that the chromatin remodeling process is highly programmed. Imaging and biochemical experiments reveal a direct histone-to-PRM1 exchange, while TNPs appear after PRM1 but precede PRM2 incorporation. This temporal uncoupling of PRM1 and PRM2 incorporation coincides with dynamic, region-specific chromatin remodeling that is not governed by histone acetylation but is instructed by the three-dimensional nuclear architecture of round spermatids. Therefore, by integrating ATAC-seq, CUT&Tag, and Hi-C, we define a compartment-encoded "blueprint" that prescribes the assembly of the mature sperm epigenome and establishes a complex molecular hierarchy for the histone-to-protamine exchange.

  PublisherOA PDFDOI

• Complementary constraints in germ and immune cells shape evolution of gene regulation and phenotype

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-30

  articleOpen accessSenior authorCorresponding

  Abstract New mutations arise in germ cells and must preserve fertility while altering somatic phenotype to confer a fitness advantage. To understand how whole organisms balance these constraints, we generated mice with humanized noncoding promoter sequence at Traf6 , an NF-κB pathway component with recently diverged chromatin state in mouse germ cells. The humanized allele (Traf6 h ) reinstated human-like expression in germ and immune cells, which we traced to a 13 base pair deletion that impairs CTCF binding. Traf6 h had no effect on fertility but induced a sensitized innate immune response to endotoxin. Other NF-κB pathway genes followed a similar pattern, suggesting that their expression has evolved in tandem and consistent with known mouse-human differences in inflammatory response. Our results reveal distinct roles for germ and immune cells in shaping gene regulatory evolution, where immune cells quickly adjust phenotype, enabling selection, while germ cells robustly maintain fertility despite changing expression levels, enabling inheritance.

  PublisherDOI

• PROTAMINE 2 DEFICIENT SPERM CAUSE ABNORMAL EMBRYOGENESIS IN MICE

  Fertility and Sterility · 2025-06-29

  articleSenior author
  PublisherDOI

• Author response for "TNFRSF1A and NCF1 May Act as Hub Genes in Mastitis"

  2025-02-14

  peer-reviewSenior author
  PublisherDOI

• H3K4me3 amplifies transcription at intergenic active regulatory elements

  Genes & Development · 2025-08-18 · 5 citations

  articleOpen accessSenior author

  Mammalian genomes undergo pervasive transcription in both genic and intergenic regions. Trimethylation of histone H3 lysine 4 (H3K4me3) is a deeply conserved and functionally important histone modification enriched at transcriptionally active promoters, where it facilitates RNA polymerase activity. H3K4me3 is also commonly found in intergenic regions, where its role is poorly understood. We interrogated the role of H3K4me3 at intergenic regulatory elements by using epigenetic editing to efficiently deposit H3K4me3 at intergenic loci. We found that H3K4me3 amplifies RNA polymerase activity and is actively remodeled at intergenic regions, shedding light on these important but poorly understood regions of the genome.

  PublisherOA PDFDOI

• Profiling Histone Modifications in Differentiating Mouse Spermatogonia with CUT&Tag

  Methods in molecular biology · 2025-01-01

  articleSenior author
  PublisherDOI

• Mechanisms for Maintaining Cell Identity in C.elegans Olfactory Neurons

  Digital Commons - RU (Rockefeller University) · 2025-09-08

  articleOpen access1st authorCorresponding

  Maintenance of cell identity is a complex process that depends on developmentally determined transcriptional states and on environmental input. In neurons, which are both highly differentiated and highly sensitive to external stimuli, maintenance of identity is especially challenging. In this thesis, I describe the isolation and characterization of several genes involved in maintaining the identities of two olfactory neuron subtypes, AWCON and AWCOFF, in the nematode Caenorhabditis elegans. The AWCON and AWCOFF identities are specified by a stochastic decision during embryogenesis, but several of the genes involved in this embryonic decision are subsequently downregulated. Additional mechanisms must therefore act to maintain the AWCON and AWCOFF cell fates. I cloned and characterized a transcription factor, nsy-7, that was required to maintain expression of the AWCON marker str-2. nsy-7 mutants also misexpressed the AWCOFF marker srsx-3 in both AWCs. The chemotaxis phenotype of these mutants indicated that their defects in str-2 and srsx-3 expression corresponded to a more general change in cell identity from AWCON to AWCOFF. nsy-7 expression was restricted to AWCON by the signaling pathway that controls the initial fate decision. I collaborated with the Bulyk lab to discover a specific seven-nucleotide DNA sequence bound by the NSY-7 protein. This sequence was present in the srsx-3 promoter and required for NSY-7-mediated repression of srsx-3 in AWCON. Using this sequence, I was also able to predict new transcriptional targets of NSY-7. In a screen to identify additional genes affecting maintenance of str-2 and srsx-3 expression, I isolated nineteen mutants, including the uncharacterized conserved transcription factor hmbx-1 and components of the TGFβ pathway. I showed that TGFβ signaling is required continuously in adults to maintain srsx-3 expression and depends on dauer pheromone, an external sensory cue. I then identified new AWCON- and AWCOFF-specific markers and examined the extent to which changes in expression of str-2 or srsx-3 correlate with larger-scale changes in gene expression in the two AWC neurons. Together, my results indicate that several interlocking genetic pathways combine to maintain the AWCON and AWCOFF cell identities, including several factors not previously known to be involved in this process.

  PublisherDOI

• SMARCA5 restricts chromatin accessibility to promote male meiosis and fertility in mammals

  Proceedings of the National Academy of Sciences · 2025-07-31 · 6 citations

  articleOpen accessSenior authorCorresponding

  Establishment of correct chromatin configuration in male meiosis is essential for sperm formation and male fertility. However, how chromatin remodeling contributes to meiotic progression in male germ cells is not well understood. Here, we find that the ISWI family ATP-dependent chromatin remodeling factor SMARCA5 (SNF2H) plays a critical role in regulating meiotic prophase progression during spermatogenesis in mice. Male mice with germ cell-specific depletion of SMARCA5 are infertile and unable to form sperm. Conditional knockout of Smarca5 results in meiotic progression failure, with abnormal spermatocytes appearing at the pachytene stage of meiosis I and subsequent accumulation of defects in chromosome synapsis, DNA repair, and transposon control, along with elevated rates of apoptosis. SMARCA5 interacts with known cofactors BAZ1A/ACF and BAZ2A/TIP5, as well as numerous DNA repair and recombination factors, in the testis. Single cell RNA sequencing confirmed failure to achieve a normal transcriptional state in premeiotic spermatogonia and during meiotic prophase, with reduced levels of meiotic gene transcripts and increasingly aberrant transcriptional states at later stages of spermatogenic development. Transcriptional misregulation in meiotic prophase was preceded by a widespread increase in chromatin accessibility in spermatogonia at promoters and repeat elements. Our findings suggest that SMARCA5 restricts chromatin accessibility in male germ cells to guide appropriate chromatin remodeling during meiotic recombination, contrasting with its role promoting chromatin accessibility during female meiosis.

  PublisherDOI

Recent grants

• Sex chromosome control of chromatin in the gametes

  NIH · $126k · 2013–2016

• NIH Grant F30MH084482

  NIH · $139k · 2012

• Germline Utx mutation as a model for transgenerational epigenetic inheritance

  NIH · $2.0M · 2020–2025

Frequent coauthors

• David C. Page

  Massachusetts Institute of Technology

  19 shared

• TuKiet T. Lam

  Yale University

  14 shared

• Zachary D. Smith

  12 shared

• Dirk G. de Rooij

  12 shared

• David C. Page

  Howard Hughes Medical Institute

  11 shared

• Benjamin William Walters

  Yale University

  10 shared

• Cornelia I. Bargmann

  Rockefeller University

  10 shared

• Leah M. Okumura

  Whitehead Institute for Biomedical Research

  9 shared

Awards & honors

• NIH Kirschstein postdoctoral fellowship
• Hope Funds for Cancer Research postdoctoral fellow
• Burroughs Wellcome Career Award for Medical Scientists (2015…
• Searle Scholar (2019)
• Pew Biomedical Scholar (2021)