About

Michael (Geoff) Rosenfeld is a Professor of Medicine at UC San Diego, with a research focus on the regulatory landscape of the aging human ovary, immune and beta cell dysregulation underlying type 1 diabetes, and the roles of HSV1 transcripts in Alzheimer's disease pathogenesis and therapy. His work involves multi-omics analyses, gene regulation, enhancer codes, and chromosomal architecture to understand complex biological processes and disease mechanisms. Rosenfeld has contributed to advancing knowledge in gene transcription, enhancer specificity, and genome architecture, with numerous funded projects supported by NIH grants. His research integrates molecular biology, genetics, and translational approaches to address critical questions in aging, neurodegeneration, and cancer.

Research topics

• Genetics
• Cell biology
• Biology
• Computational biology
• Medicine
• Internal medicine
• Cancer research

Selected publications

• Endogenous Real Time Imaging Reveals Dynamic Chromosomal Mobility During Ligand-Mediated Transcriptional Burst Events

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-19

  preprintOpen accessSenior authorCorresponding

  Enhancers serve as the major genomic elements regulating mammalian signal-dependent transcriptional programs, characterized by alternating periods of target gene "bursting" and "non-busting" that require investigation of induced enhancer condensates and locus motility in real time to provide dynamic insights into signal/ligand-dependent regulatory events. Here, endogenous live cell imaging has revealed the altered chromosomal dynamics/condensate formation occurring during estrogen receptor α (ERα)-dependent target gene bursting/post-bursting and chronic activation events. Simultaneous DNA/RNA endogenous live imaging reveals that an increased mobility of acutely ERα-stimulated loci observed during the bursting phase is, unexpectedly, further increased in the subsequent non-burst phase. Single molecule tracking (SMT) of ERα shows that the relatively high-burst, lower-mobility acute state was indeed enriched for high-viscosity, 1,6-hexanediol-sensative ERα molecules in a low sub-diffusive confined state with enhanced condensate formation during burst activation. Consistent with this, blocking transcription with flavopiridol shifts DNA tracks into a non-confined state. Differential DNA kinetics during burst vs non-burst has provided a strategy to assess altered condensate formation during gene activation events. (165).

  PublisherOA PDFDOI

• AAV Kills Dividing Cells by Depleting PARP1 and Other DNA Damage Response Proteins

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-15 · 2 citations

  preprintOpen access

  Recombinant adeno-associated virus (rAAV) is a replication-defective viral vector used in hundreds of human gene therapy trials, resulting in five FDA-approved therapies. Despite this success, rAAV-based gene therapies suffer from dose-limiting toxicities, resulting in several severe adverse reactions, including death. Previously, we discovered that rAAV rapidly kills mouse NPCs in vitro and in vivo. This vector contains a minimal genome comprised of 145-base pair inverted terminal repeats (ITRs) with a T-shaped hairpin structure that appears to be necessary and sufficient for this toxicity. However, the mechanism for AAV ITR toxicity is not known, and there have been few attempts to engineer ITRs to attenuate rAAV toxicity. In the current study, we explore the molecular mechanisms that drive dose-dependent rAAV toxicity in dividing human NPCs (hNPCs) and test whether disrupting these mechanisms mitigates this toxicity. Recombinant AAV infection induces aberrant cell cycle progression with activation of the ATM /CHK1/CHK2 pathway and expression of the DNA damage markers γH2AX and 53BP1. Affinity-based proteomics indicate that AAV ITRs bind to Poly-(ADP-Ribose)polymerase 1 (PARP1) and other DNA damage response (DDR) proteins involved in single-strand break repair (SSBR). Recombinant AAV infection attenuates poly-(ADP-ribose) (PAR) formation and mimics the antiproliferative effects of pharmacological PARP inhibitors used in cancer therapy. Moreover, treatment of hNPCs with PARP inhibitors is sufficient to reproduce many features of rAAV-induced toxicity. Finally, we demonstrate that eliminating the T-shaped hairpin within the AAV ITR reduces binding to SSBR proteins and the resulting rAAV toxicity. These findings suggest that rAAV infection induces replication stress and cell death in dividing hNPCs by functionally depleting PARP1 and other DDR proteins that are essential for DNA replication. This work fills substantial gaps in the understanding of the mechanisms of rAAV toxicity and has important implications for the development of safer rAAV-based human gene therapies.

  PublisherOA PDFDOI

• Endogenous Real Time Imaging Reveals Dynamic Chromosomal Mobility During Ligand-Mediated Transcriptional Burst Events

  eLife · 2025-10-27

  articleOpen accessSenior author

  Enhancers serve as the major genomic elements regulating mammalian signal-dependent transcriptional programs, characterized by alternating periods of target gene “bursting” and “non-busting” that require investigation of induced enhancer condensates and locus motility in real time to provide dynamic insights into signal/ligand-dependent regulatory events. Here, endogenous live cell imaging has revealed the altered chromosomal dynamics/condensate formation occurring during estrogen receptor α (ERα)-dependent target gene bursting/post-bursting and chronic activation events. Simultaneous DNA/RNA endogenous live imaging reveals that an increased mobility of acutely ERα-stimulated loci observed during the bursting phase is, unexpectedly, further increased in the subsequent non-burst phase. Single molecule tracking (SMT) of ERα shows that the relatively high-burst, lower-mobility acute state was indeed enriched for high-viscosity, 1,6-hexanediol-sensative ERα molecules in a low sub-diffusive confined state with enhanced condensate formation during burst activation. Consistent with this, blocking transcription with flavopiridol shifts DNA tracks into a non-confined state. Differential DNA kinetics during burst vs non-burst has provided a strategy to assess altered condensate formation during gene activation events. (165)

  PublisherDOI

• Liquid-liquid phase separation mediated immune evasion of RSV against OAS-RNase L pathway

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-24

  preprintOpen access

  Abstract Respiratory syncytial virus (RSV) infection is the major cause of severe respiratory illnesses in infants and older adults. RSV forms phase-separated biomolecular condensates called inclusion bodies (IBs), which serve as hubs for viral replication. However, the contribution of IBs to host immune response evasion remains elusive. We report that RSV IBs protect viral RNA from the 2′-5′ oligoadenylate synthetase (OAS)-RNase L pathway, a critical antiviral defense mechanism that cleaves viral and cellular RNAs. RSV infection did not activate the OAS-RNase L pathway, and ectopically activated RNase L did not suppress viral replication. In RSV-infected cells, double-stranded RNA (dsRNA) was efficiently sequestered within liquid–liquid phase separation (LLPS)-mediated IBs, rendering its detection challenging. LLPS perturbation caused dsRNA release from IBs into the cytosol. dsRNA extracted from infected cells, which lacked LLPS shielding, triggered OAS-RNase L pathway activation. Thus, LLPS-driven IBs structurally sequester viral RNA, facilitating RSV to evade RNase-dependent genomic RNA degradation mediated by the OAS-RNase L antiviral pathway.

  PublisherOA PDFDOI

• Nonproteolytic ubiquitination regulates chromatin occupancy by the NCoR/SMRT/HDAC3 corepressor complex in MCF-7 breast cancer cells

  Proceedings of the National Academy of Sciences · 2025-04-30 · 3 citations

  articleOpen accessCorresponding

  Tight regulation of gene expression is achieved through the coordinated action of transcription factors and cofactors that often can act as both repressors and activators in response to regulatory signals, with their activity modulated by context-specific signal transduction pathways that also impinge on their transient and cyclical recruitment to chromatin. However, the mechanisms underlying the intricate interplay between the regulatory strategies controlling cofactors' activity and localization across subcellar domains remain poorly understood. Here, we investigated the role of G-Protein Pathway Suppressor 2 (GPS2), a transcriptional cofactor critical for maintaining cellular homeostasis via regulation of mitochondrial biogenesis, stress response, lipid metabolism, insulin signaling, and inflammation, in MCF-7 breast cancer cells. By integration of biochemical assays with genome-wide RNA sequencing and Chromatin immunoprecipitation-Seq analyses, we show that nuclear GPS2 is required for licensing histone deacetylase 3 recruitment to chromatin via restricted ubiquitination by tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase previously shown to regulate the switch from repressive to activating functions of the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complex and here unexpectedly found to translocate to the nucleus in response to IL-1β stimulation. Nuclear TRAF6 is recruited to chromatin via direct interaction with the corepressors NCoR/SMRT, and TRAF6-mediated ubiquitination of TGF-beta activated kinase 1 (MAP3K7) binding protein 2 (TAB2), a facultative component of the NCoR/SMRT complex, contributes to corepressor clearance from target regulatory regions. Together, these results reveal an exquisite mechanism for coordinating the local regulation of cofactor activity with proinflammatory signaling pathways.

  PublisherOA PDFDOI

• An eRNA transcription checkpoint for diverse signal-dependent enhancer activation programs

  Nature Genetics · 2025-04-01 · 3 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Ligand-specific regulation of a binary enhancer code dictating cellular senescence

  Proceedings of the National Academy of Sciences · 2025-06-10 · 3 citations

  articleOpen accessCorresponding

  Cellular senescence, a major contributor to aging and age-related pathologies, is characterized by irreversible proliferative arrest and a disease-linked, proinflammatory profile known as the Senescence Associated Secretory Phenotype (SASP). A critical unanswered question is whether these properties are regulated by specific enhancer subsets, potentially licensing strategies that selectively block deleterious SASP components. Here, we identify two functionally distinct and independently regulated enhancer programs underlying senescence that are controlled by different TGF-β family ligands. Whereas Activin A stimulates recruitment of nuclear factor IA/C (NFIA/C) and SMAD2/3 transcription factors to an enhancer network that induces proliferation arrest, TGF-β2 promotes SMAD2/3-mediated suppression of a p65-dependent enhancer cohort driving the SASP. We have also uncovered reciprocal SMAD2/3-super-enhancer-regulated feedback loops that govern expression of the TGF-β2 ( TGFB2) and Activin A ( INHBA ) transcription units, both of which are significantly up-regulated in replicative senescence. The characteristic enhancer usage and transcriptional landscape of high-passage senescent cells are sensitive to rapamycin treatment, discontinuation of which results in robust but selective senescent enhancer activation and exacerbation of the SASP. Collectively, this study uncovers separable enhancer programs and their key constituent transcription factors that contribute to the canonical features of cellular senescence, potentially informing the development of SASP-targeted therapies.

  PublisherOA PDFDOI

• Endogenous Real Time Imaging Reveals Dynamic Chromosomal Mobility During Ligand-Mediated Transcriptional Burst Events

  eLife · 2025-10-27

  articleOpen accessSenior author

  Enhancers serve as the major genomic elements regulating mammalian signal-dependent transcriptional programs, characterized by alternating periods of target gene “bursting” and “non-busting” that require investigation of induced enhancer condensates and locus motility in real time to provide dynamic insights into signal/ligand-dependent regulatory events. Here, endogenous live cell imaging has revealed the altered chromosomal dynamics/condensate formation occurring during estrogen receptor α (ERα)-dependent target gene bursting/post-bursting and chronic activation events. Simultaneous DNA/RNA endogenous live imaging reveals that an increased mobility of acutely ERα-stimulated loci observed during the bursting phase is, unexpectedly, further increased in the subsequent non-burst phase. Single molecule tracking (SMT) of ERα shows that the relatively high-burst, lower-mobility acute state was indeed enriched for high-viscosity, 1,6-hexanediol-sensative ERα molecules in a low sub-diffusive confined state with enhanced condensate formation during burst activation. Consistent with this, blocking transcription with flavopiridol shifts DNA tracks into a non-confined state. Differential DNA kinetics during burst vs non-burst has provided a strategy to assess altered condensate formation during gene activation events. (165)

  PublisherDOI

• Molecular and Genetic Insights Into Human Ovarian Aging From Single-Nuclei Multi-omics Analyses

  Obstetrical & Gynecological Survey · 2025-03-01 · 1 citations

  article

  (Abstracted from Nat Aging 2024. doi: 10.1038/s43587-024-00762-5) Ovaries are the crux of the female reproductive system and are the first organs to show signs of aging and thus the slowing of reproductive processes, characterized by a reduced number and quality of oocytes. The more a woman ages, the higher the risk of infertility or aneuploidy and congenital disabilities in their children.

  PublisherDOI

• Enhancer–promoter specificity in gene transcription: molecular mechanisms and disease associations

  Experimental & Molecular Medicine · 2024-04-25 · 38 citations

  reviewOpen access

  Although often located at a distance from their target gene promoters, enhancers are the primary genomic determinants of temporal and spatial transcriptional specificity in metazoans. Since the discovery of the first enhancer element in simian virus 40, there has been substantial interest in unraveling the mechanism(s) by which enhancers communicate with their partner promoters to ensure proper gene expression. These research efforts have benefited considerably from the application of increasingly sophisticated sequencing- and imaging-based approaches in conjunction with innovative (epi)genome-editing technologies; however, despite various proposed models, the principles of enhancer-promoter interaction have still not been fully elucidated. In this review, we provide an overview of recent progress in the eukaryotic gene transcription field pertaining to enhancer-promoter specificity. A better understanding of the mechanistic basis of lineage- and context-dependent enhancer-promoter engagement, along with the continued identification of functional enhancers, will provide key insights into the spatiotemporal control of gene expression that can reveal therapeutic opportunities for a range of enhancer-related diseases.

  PublisherOA PDFDOI

Recent grants

• Phase Separation: A New Phase in Decoding Enhancer-dependent Critical Transcriptional Programs by Nuclear Receptors

  NIH · $4.2M · 1982–2025

• Chromosomal Boundary Alterations Driving Transcriptional Dysregulation in Brain Disorders

  NIH · $2.4M · 2016–2022

• NIH Grant R01NS048243

  NIH · $903k · 2008

• NIH Grant R01HL065445

  NIH · $5.3M · 2014

• Repressors in Prostate Cancer

  NIH · $3.2M · 2002–2013

Frequent coauthors

• Christopher K. Glass

  University of California, San Diego

  244 shared

• Kenneth A. Ohgi

  University of California, San Diego

  146 shared

• Ronald M. Evans

  Salk Institute for Biological Studies

  137 shared

• David W. Rose

  The University of Texas at Tyler

  106 shared

• Dimple Notani

  National Centre for Biological Sciences

  91 shared

• Ranveer Singh Jayani

  86 shared

• Bogdan Paşaniuc

  University of California, Los Angeles

  82 shared

• Wenbo Li

  82 shared

Education

• Ph.D., Molecular and Computational Biology

  University of California, San Diego

  1996

• M.S., Molecular and Computational Biology

  University of California, San Diego

  1992

• B.S., Biology

  University of California, San Diego

  1990