About

The Knoepfler Lab conducts developmental biology, stem cell, and cancer research with a focus on chromatin and epigenetic mechanisms at the UC Davis School of Medicine, Sacramento, CA 95817. We are particularly interested in regulation of normal brain growth and how epigenomic programming goes awry in childhood brain tumors and microcephaly.

Research topics

• Genetics
• Biology
• Cell biology
• Computational biology
• Cancer research
• Political Science
• Public relations
• Cognitive science
• Medicine
• Psychology

Selected publications

• Evidence for coordinate CTCF and histone H3.3 activities in K27M diffuse midline gliomas

  Acta Neuropathologica Communications · 2026-05-02

  articleOpen accessSenior author

  Up to 80% of diffuse midline gliomas (DMGs) are characterized by a lysine to methionine driver mutation (K27M) in the tail of histone variant H3.3, pointing to likely roles for epigenetic mechanisms in K27M-driven tumorigenesis. Understanding the effects of mutant histone H3.3 on the complex patterns of histone modifications and interactions with chromatin structure and modifying enzymes is essential to developing effective combination treatment therapies for K27M DMG such as targeting multiple epigenetic enzymes at once. Here, using a genomics approach, we identified combinatorial patterns of epigenetic modifications that are affected by mutant H3.3 in DMG. We also characterized a strong association between H3.3 and the structural chromatin regulator CTCF, finding that mutant H3.3 leads to ectopic binding of CTCF at many additional sites across the genome in DMG. Notably, a number of these ectopic CTCF binding events occur within the HOX gene loci and are associated with an increase in H3K27me3 levels at bivalent domains and a decrease in HOX gene expression. We also find an association of H3.3 and CTCF at genomic sites adjacent to regions with active or repressive modifications, suggesting a potential role for these two factors in segmenting the chromatin and regulating, perhaps insulating, different types of domains. Together our data suggest that H3.3 K27M both affects epigenetic marks and chromatin organization in part through interaction with CTCF and point to a potentially novel contributory role for CTCF in promoting oncogenesis in DMG. These findings could have potential implications for designing therapy regimens to more effectively target the chromatin changes and genomic instability observed in H3.3K27M glioma cells.

  PublisherDOI

• Why hype for autism stem cell therapies continues despite dead ends

  The Transmitter · 2025-01-01

  article1st authorCorresponding
  PublisherDOI

• Governing with public engagement: an anticipatory approach to human genome editing

  Science and Public Policy · 2024 · 9 citations

  • Political Science
  • Computational biology
  • Biology

  In response to calls for public engagement on human genome editing (HGE), which intensified after the 2018 He Jiankui scandal that resulted in the implantation of genetically modified embryos, we detail an anticipatory approach to the governance of HGE. By soliciting multidisciplinary experts' input on the drivers and uncertainties of HGE development, we developed a set of plausible future scenarios to ascertain publics values-specifically, their hopes and concerns regarding the novel technology and its applications. In turn, we gathered a subset of multidisciplinary experts to propose governance recommendations for HGE that incorporate identified publics' values. These recommendations include: (1) continued participatory public engagement; (2) international harmonization and transparency of multiple governance levers such as professional and scientific societies, funders, and regulators; and (3) development of a formal whistleblower framework.

  PublisherOA PDFDOI

• Noncanonical function of folate through folate receptor 1 during neural tube formation

  Nature Communications · 2024-02-22 · 15 citations

  articleOpen access

  Abstract Folate supplementation reduces the occurrence of neural tube defects (NTDs), birth defects consisting in the failure of the neural tube to form and close. The mechanisms underlying NTDs and their prevention by folate remain unclear. Here we show that folate receptor 1 (FOLR1) is necessary for the formation of neural tube-like structures in human-cell derived neural organoids. FOLR1 knockdown in neural organoids and in Xenopus laevis embryos leads to NTDs that are rescued by pteroate, a folate precursor that is unable to participate in metabolism. We demonstrate that FOLR1 interacts with and opposes the function of CD2-associated protein, molecule essential for apical endocytosis and turnover of C-cadherin in neural plate cells. In addition, folates increase Ca 2+ transient frequency, suggesting that folate and FOLR1 signal intracellularly to regulate neural plate folding. This study identifies a mechanism of action of folate distinct from its vitamin function during neural tube formation.

  PublisherOA PDFDOI

• Data from N-Myc Regulates a Widespread Euchromatic Program in the Human Genome Partially Independent of Its Role as a Classical Transcription Factor

  2023-03-30

  preprintOpen accessSenior author

  <div>Abstract<p>Myc proteins have long been modeled to operate strictly as classic gene-specific transcription factors; however, we find that N-Myc has a robust role in the human genome in regulating global cellular euchromatin, including that of intergenic regions. Strikingly, 90% to 95% of the total genomic euchromatic marks histone H3 acetylated at lysine 9 and methylated at lysine 4 is N-Myc–dependent. However, Myc regulation of transcription, even of genes it directly binds and at which it is required for the maintenance of active chromatin, is generally weak. Thus, Myc has a much more potent ability to regulate large domains of euchromatin than to influence the transcription of individual genes. Overall, Myc regulation of chromatin in the human genome includes both specific genes, but also expansive genomic domains that invoke functions independent of a classic transcription factor. These findings support a new dual model for Myc chromatin function with important implications for the role of Myc in cancer and stem cell biology, including that of induced pluripotent stem cells. [Cancer Res 2008;68(23):9654–62]</p></div>

  PublisherDOI

• EPCO-10. AN ONCOGENIC NEURODEVELOPMENTAL PROGRAM IN H3.3 K27M DIFFUSE MIDLINE GLIOMA INVOKES ABERRANT ASCL1-SMARCA4 EPIGENOMIC ACTIVITY

  Neuro-Oncology · 2023-11-01

  articleOpen access1st authorCorresponding

  Abstract The histone variant H3.3 K27M mutation is common in diffuse midline gliomas (DMG) and is associated with poor prognosis. While some insights into K27M epigenetic functions have emerged, much less is known about how K27M impacts chromatin structure and function, and the resulting transcriptomic consequences. Recently, we developed isogenic CRISPR-edited DMG cell lines that are wild-type for histone H3.3 that can be compared to their matched K27M lines. ATAC-seq analysis of the matched sets of isogenic WT and H3.3K27M glioma cells pointed to unique K27M-associated accessible chromatin at regions corresponding to specific neurogenesis, NOTCH, and neuronal development pathways. These domains corresponded to genes that are overexpressed in H3.3K27M compared to our isogenic wild-type cell lines. Uniquely accessible enhancers and super-enhancers corresponding to increased gene expression in H3.3K27M cells were also mapped to genes involved in neurogenesis and NOTCH signaling, suggesting that these pathways are important for tumorigenesis. Motif analysis implicates specific transcription factors as central to the neuro-oncogenic K27M signaling pathway including, in particular, ASCL1 and NEUROD1. CUT&RUN for ASCL1 defined novel target genes in DMG and BioID identified key epigenomic cofactors for ASCL1 including SMARCA4. Large-scale computational analysis of both our and other groups’ data including by chromHMM identified novel functional chromatin domains and potential looping events related to K27M as well. Overall, our findings indicate that H3.3K27M changes specific chromatin functions altering neurodevelopmental gene expression resulting in aberrant activity of an oncogenic epigenomic program. Encouragingly, this program appears at least partially reversible upon editing K27M back to wild-type, pointing to potential translational impact moving forward to targeting this pathway.

  PublisherOA PDFDOI

• Knockout tales: the versatile roles of histone H3.3 in development and disease

  Epigenetics & Chromatin · 2023 · 22 citations

  Senior authorCorresponding
  • Biology
  • Computational biology
  • Genetics

  Histone variant H3.3 plays novel roles in development as compared to canonical H3 proteins and is the most commonly mutated histone protein of any kind in human disease. Here we discuss how gene targeting studies of the two H3.3-coding genes H3f3a and H3f3b have provided important insights into H3.3 functions including in gametes as well as brain and lung development. Knockouts have also provided insights into the important roles of H3.3 in maintaining genomic stability and chromatin organization, processes that are also affected when H3.3 is mutated in human diseases such as pediatric tumors and neurodevelopmental syndromes. Overall, H3.3 is a unique histone linking development and disease via epigenomic machinery.

  PublisherOA PDFDOI

• Data from N-Myc Regulates a Widespread Euchromatic Program in the Human Genome Partially Independent of Its Role as a Classical Transcription Factor

  2023-03-30

  preprintOpen accessSenior author

  <div>Abstract<p>Myc proteins have long been modeled to operate strictly as classic gene-specific transcription factors; however, we find that N-Myc has a robust role in the human genome in regulating global cellular euchromatin, including that of intergenic regions. Strikingly, 90% to 95% of the total genomic euchromatic marks histone H3 acetylated at lysine 9 and methylated at lysine 4 is N-Myc–dependent. However, Myc regulation of transcription, even of genes it directly binds and at which it is required for the maintenance of active chromatin, is generally weak. Thus, Myc has a much more potent ability to regulate large domains of euchromatin than to influence the transcription of individual genes. Overall, Myc regulation of chromatin in the human genome includes both specific genes, but also expansive genomic domains that invoke functions independent of a classic transcription factor. These findings support a new dual model for Myc chromatin function with important implications for the role of Myc in cancer and stem cell biology, including that of induced pluripotent stem cells. [Cancer Res 2008;68(23):9654–62]</p></div>

  PublisherDOI

• Non-canonical function of folate/folate receptor 1 during neural tube formation

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-07-21

  preprintOpen access

  Abstract Folate supplementation reduces the occurrence of neural tube defects, one of the most common and serious birth defects, consisting in the failure of the neural tube to form and close early in pregnancy. The mechanisms underlying neural tube defects and folate action during neural tube formation remain unclear. Here we show that folate receptor 1 (FOLR1) is necessary for the formation of neural tube-like structures in human-cell derived neural organoids. Knockdown of FOLR1 in human neural organoids as well as in the Xenopus laevis in vivo model leads to neural tube defects that are rescued by pteroate, a folate precursor that binds to FOLR1 but is unable to participate in metabolic pathways. We demonstrate that FOLR1 interacts with and opposes the function of CD2-associated protein (CD2AP), a molecule that we find is essential for apical endocytosis and the spatiotemporal turnover of the cell adherens junction component C-cadherin in neural plate cells. The counteracting action of FOLR1 on these processes is mediated by regulating CD2AP protein level via a degradation-dependent mechanism. In addition, folate and pteroate increase Ca 2+ transient frequency in the neural plate in a FOLR1-dependent manner, suggesting that folate/FOLR1 signal intracellularly to regulate neural plate folding. This study identifies a mechanism of action of folate distinct from its vitamin function during neural tube formation.

  PublisherOA PDFDOI

• Supplementary Figure 1 from N-Myc Regulates a Widespread Euchromatic Program in the Human Genome Partially Independent of Its Role as a Classical Transcription Factor

  2023-03-30

  preprintOpen accessSenior author

  Supplementary Figure 1 from N-Myc Regulates a Widespread Euchromatic Program in the Human Genome Partially Independent of Its Role as a Classical Transcription Factor

  PublisherDOI

Recent grants

• Targeting a novel H3.3 epigenetic switch to regulate health and disease

  NIH · $1.4M · 2016–2021

• NIH Grant R01GM100782

  NIH · $1.4M · 2017

• Targeting the Mutant H3.3 Pathway in Glioma

  NIH · $1.8M · 2018–2024

• NIH Grant K01CA114400

  NIH · $720k · 2010

• Targeting the Mutant H3.3 Pathway in Glioma

  NIH · $332k · 2018–2023

Frequent coauthors

• Alice Wey

  30 shared

• Kelly Bush

  Shriners Hospitals for Children - Northern California

  29 shared

• Bonnie L. Barrilleaux

  28 shared

• Robert N. Eisenman

  Fred Hutch Cancer Center

  25 shared

• Rachel Herndon Klein

  University of California, Davis

  24 shared

• Priyanka Somanath

  18 shared

• Rebecca Cotterman

  University of California, Davis

  17 shared

• Nichole Lewis

  University of California, Davis

  15 shared

Awards & honors

• Leukemia and Lymphoma Society Special Fellowship (2002-2005)
• Howard Temin Award, NCI (2005-2010)
• Brain Tumor Society Award (2007-2008)
• Steven C. Higgins Leadership Chair of Research
• March of Dimes Basil O'Conner Starter Scholar Award (2008-20…