About

Sam Gu is an Associate Professor in the Department of Molecular Biology and Biochemistry at Rutgers University. His research primarily focuses on computational biology, epigenetics and chromatin, gene regulation, reproduction and gametogenesis, and RNA/ribosome biology. The Gu lab investigates the mechanisms of epigenetic regulation, particularly how epigenetic memory is triggered and transmitted through generational boundaries, using both experimental and computational approaches with the nematode C. elegans. A key aspect of his research involves RNA-induced chromatin modification, which can last for multiple generations after initial RNA exposure in C. elegans. His work aims to expand discoveries from C. elegans into human biology, with a focus on novel modes of RNA-chromatin interaction and epigenetic inheritance. His research addresses fundamental questions about whether non-DNA sequence information can be heritable and influence phenotypes across generations, contributing to the understanding of gene regulation and developmental control.

Research topics

• Genetics
• Biology
• Cell biology

Selected publications

• Two H3K23 histone methyltransferases, SET-32 and SET-21, function synergistically to promote nuclear RNAi-mediated transgenerational epigenetic inheritance in <i>Caenorhabditis elegans</i>

  Genetics · 2024-12-10 · 6 citations

  articleOpen accessSenior author

  Nuclear RNAi in Caenorhabditis elegans induces a set of transgenerationally heritable marks of H3K9me3, H3K23me3, and H3K27me3 at the target genes. The function of H3K23me3 in the nuclear RNAi pathway is largely unknown due to the limited knowledge of H3K23 histone methyltransferase (HMT). In this study we identified SET-21 as a novel H3K23 HMT. By taking combined genetic, biochemical, imaging, and genomic approaches, we found that SET-21 functions synergistically with a previously reported H3K23 HMT SET-32 to deposit H3K23me3 at the native targets of germline nuclear RNAi. We identified a subset of native nuclear RNAi targets that are transcriptionally activated in the set-21;set-32 double mutant. SET-21 and SET-32 are also required for robust transgenerational gene silencing induced by exogenous dsRNA. The set-21;set-32 double mutant strain exhibits an enhanced temperature-sensitive mortal germline phenotype compared to the set-32 single mutant, while the set-21 single mutant animals are fertile. We also found that HRDE-1 and SET-32 are required for cosuppression, a transgene-induced gene silencing phenomenon, in C. elegans germline. Together, these results support a model in which H3K23 HMTs SET-21 and SET-32 function cooperatively as germline nuclear RNAi factors and promote the germline immortality under the heat stress.

  PublisherOA PDFDOI

• Two H3K23 histone methyltransferases, SET-32 and SET-21, function synergistically to promote nuclear RNAi-mediated transgenerational epigenetic inheritance in <i>Caenorhabditis elegans</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-06 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Nuclear RNAi in C. elegans induces a set of transgenerationally heritable marks of H3K9me3, H3K23me3, and H3K27me3 at the target genes. The function of H3K23me3 in the nuclear RNAi pathway is largely unknown due to the limited knowledge of H3K23 histone methyltransferase (HMT). In this study we identified SET-21 as a novel H3K23 HMT. By taking combined genetic, biochemical, imaging, and genomic approaches, we found that SET-21 functions synergistically with a previously reported H3K23 HMT SET-32 to deposit H3K23me3 at the native targets of germline nuclear RNAi. We identified a subset of native nuclear RNAi targets that are transcriptionally activated in the set-21;set-32 double mutant. SET-21 and SET-32 are also required for robust transgenerational gene silencing induced by exogenous dsRNA. The set-21;set-32 double mutant strain exhibits an enhanced temperature-sensitive mortal germline phenotype compared to the set-32 single mutant, while the set-21 single mutant animals are fertile. We also found that HRDE-1 and SET-32 are required for cosuppression, a transgene-induced gene silencing phenomenon, in C. elegans germline. Together, these results support a model in which H3K23 HMTs SET-21 and SET-32 function cooperatively to ensure the robustness of germline nuclear RNAi and promotes the germline immortality under the heat stress.

  PublisherOA PDFDOI

• SPE-51, a sperm-secreted protein with an immunoglobulin-like domain, is required for fertilization in C. elegans

  Current Biology · 2023-07-01 · 12 citations

  letterOpen access
  PublisherOA PDFDOI

• Target-dependent siRNA suppression distinguishes self from non-self endogenous siRNAs in <i>C. elegans</i> germline

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-01-26 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Despite their prominent role in transposon silencing, expression of endo-siRNAs is not limited to the “non-self” DNA elements. Transcripts of protein-coding genes (“self” DNA) in some cases also produce endo-siRNAs in yeast, plants, and animals [1]. How cells distinguish these two populations of siRNAs to prevent unwanted silencing of self-genes in animals is not well understood. To address this question, we examined the expression of ectopic siRNAs from an LTR retrotransposon in C. elegans germline. We found that the abundance of ectopic siRNAs was dependent on their homologous target genes: ectopic siRNAs against genes expressed only in somatic cells can be abundantly expressed. In contrast, ectopic siRNAs against germline-expressed genes are often suppressed. This phenomenon, which we termed “target-directed siRNA suppression”, is dependent on the target mRNA and requires germline P-granule components. We found that siRNA suppression can also occur to naturally produced endo-siRNAs. We suggest that siRNA suppression plays an important role in regulating siRNA expression and preventing self-genes from aberrant epigenetic silencing.

  PublisherOA PDFDOI

• Target-dependent suppression of siRNA production modulates the levels of endogenous siRNAs in the <i>Caenorhabditis elegans</i> germline

  Development · 2022 · 9 citations

  Senior authorCorresponding
  • Biology
  • Genetics
  • Cell biology

  Despite the prominent role of endo-siRNAs in transposon silencing, their expression is not limited to these 'nonself' DNA elements. Transcripts of protein-coding genes ('self' DNA) in some cases also produce endo-siRNAs in yeast, plants and animals. How cells distinguish these two populations of siRNAs to prevent unwanted silencing of active genes in animals is not well understood. To address this question, we inserted various self-gene or gfp fragments into an LTR retrotransposon that produces abundant siRNAs and examined the propensity of these gene fragments to produce ectopic siRNAs in the Caenorhabditis elegans germline. We found that fragments of germline genes are generally protected from production of ectopic siRNAs. This phenomenon, which we termed 'target-directed suppression of siRNA production' (or siRNA suppression), is dependent on the germline expression of target mRNA and requires germline P-granule components. We found that siRNA suppression can also occur in naturally produced endo-siRNAs. We suggest that siRNA suppression plays an important role in regulating siRNA expression and preventing self-genes from aberrant epigenetic silencing. This article has an associated 'The people behind the papers' interview.

  PublisherOA PDFDOI

• Reprogramming the piRNA pathway for multiplexed and transgenerational gene silencing in C. elegans

  Nature Methods · 2022 · 54 citations

  • Biology
  • Genetics
  • Cell biology
  PublisherOA PDFDOI

• SPE-51, a sperm secreted protein with an Immunoglobulin-like domain, is required for sperm-egg fusion in <i>C. elegans</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2021-07-08 · 2 citations

  preprintOpen access

  Abstract Despite the importance of fertilization, the molecular basis of sperm-egg interaction is not well understood. In a forward genetics screen for fertility mutants in Caenorhabditis elegans we identified spe-51 . Mutant worms make sperm that are unable to fertilize the oocyte but otherwise normal by all available measurements. The spe-51 gene encodes a secreted protein that includes an immunoglobulin (Ig)-like domain and a hydrophobic sequence of amino acids. The SPE-51 protein acts cell-autonomously and localizes to the surface of the spermatozoa. This is the first example of a secreted protein required for the interactions between the sperm and egg with genetic validation for a specific function in fertilization. Our analyses of these genes begin to build a paradigm for sperm-secreted or reproductive tract-secreted proteins that coat the sperm surface and influence their survival, motility, and/or the ability to fertilize the egg.

  PublisherOA PDFDOI

• Author response: Caenorhabditis elegans nuclear RNAi factor SET-32 deposits the transgenerational histone modification, H3K23me3

  2020-05-28 · 1 citations

  peer-reviewOpen accessSenior author
  PublisherDOI

• <i>C. elegans</i> nuclear RNAi factor SET-32 deposits the transgenerational heritable histone modification, H3K23me3

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-02-20

  preprintOpen accessSenior authorCorresponding

  Abstract Nuclear RNAi provides a highly tractable system to study RNA-mediated chromatin changes and epigenetic inheritance. Recent studies have indicated that the regulation and function of nuclear RNAi-mediated heterochromatin are highly complex. Our knowledge of histone modifications and the corresponding histone modifying enzymes involved in the system remains limited. In this study, we show that the heterochromatin mark, H3K23me3, is induced by nuclear RNAi at both exogenous and endogenous targets in C. elegans . In addition, dsRNA-induced H3K23me3 can be inherited for four generations. We demonstrate that the histone methyltransferase SET-32, methylates H3K23 in vitro . Both set-32 and the germline nuclear RNAi Argonaute, hrde-1 , are required for nuclear RNAi-induced H3K23me3 in vivo . Our data poise H3K23me3 as an additional chromatin modification in the nuclear RNAi pathway and provides the field with a new target for uncovering the role of heterochromatin in transgenerational epigenetic silencing.

  PublisherOA PDFDOI

• Caenorhabditis elegans nuclear RNAi factor SET-32 deposits the transgenerational histone modification, H3K23me3

  eLife · 2020 · 62 citations

  Senior authorCorresponding
  • Biology
  • Genetics
  • Cell biology

  . Our data poise H3K23me3 as an additional chromatin modification in the nuclear RNAi pathway and provides the field with a new target for uncovering the role of heterochromatin in transgenerational epigenetic silencing.

  PublisherDOI

Frequent coauthors

• Julie Ni

  Rutgers, The State University of New Jersey

  26 shared

• Andrew Fire

  Stanford University

  16 shared

• Natallia Kalinava

  15 shared

• Esteban Chen

  Rutgers, The State University of New Jersey

  10 shared

• Shinichi Morishita

  The University of Tokyo

  9 shared

• Taro Saito

  Tokyo Metropolitan University

  6 shared

• Kimberly Peterman

  6 shared

• Shinichi Hashimoto

  Kagoshima University

  6 shared

Education

• PhD, Molecular, Cell and Developmental Biology

  University of California Santa Cruz

  2007