About

Robert (Bob) T Schultz, PhD, is a Professor of Clinical Psychology in Pediatrics (Developmental and Behavioral Pediatrics) at the Perelman School of Medicine at the University of Pennsylvania. He serves as the Director of the Center for Autism Research at the Children's Hospital of Philadelphia, where his research focuses on understanding the biological causes of autism spectrum disorders (ASD) and related developmental disabilities (DDs). His work aims to identify biomarkers that moderate treatment outcomes and to explore the relationships between genes, brain function, behavior, and development in these conditions. Schultz's research employs various neuroimaging techniques such as sMRI, fMRI, DTI, and ERP, along with genotyping, eye tracking, and clinical assessments, to study large samples of research volunteers with ASD, with the goal of uncovering critical insights into the heterogeneity of ASD and its comorbidities. Schultz's contributions include examining the neurofunctional models of autism and Asperger syndrome through neuroimaging, investigating social perception deficits, and exploring the neural underpinnings of social motivation and reward processing in autism. His work has significantly advanced the understanding of the relationships between genetic factors, brain structure and function, and behavioral phenotypes in autism and related developmental disorders. He has authored numerous publications that have shaped current perspectives on the neurobiological and genetic basis of autism, emphasizing large-scale data collection and analysis to inform more effective treatments and interventions.

Research topics

• Biology
• Cell biology
• Chemistry
• Genetics
• Molecular biology

Selected publications

• Polycomb shapes active chromatin and promoter bivalency during ovarian reserve formation and activation

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-25

  articleOpen access

  The ovarian reserve, a finite pool of long-lived non-growing oocytes established at birth, determines female reproductive lifespan, yet how these oocytes establish long-term quiescence while retaining the capacity for future growth and embryogenesis remains poorly understood. Here, we define a regulatory logic by which Polycomb repressive complexes shape stage-specific active chromatin remodeling during ovarian reserve formation and early oocyte growth. During ovarian reserve formation, H3K27ac, an active promoter- and enhancer-associated mark, undergoes extensive genome-wide redistribution. A key feature of this transition is CpG island promoter remodeling, in which many loci lose H3K27ac while gaining PRC1-dependent H2AK119ub, a repressive mark. This early reprogramming is followed during oocyte growth by acquisition of PRC2-dependent H3K27me3, de novo establishment of bivalent promoters, and protection of promoter regions from de novo DNA methylation. Oocyte growth is also accompanied by broad gains in both H3K27ac and H3K4me3, an active promoter-associated mark. Analyses of PRC1- and PRC2-deficient oocytes reveal unequal Polycomb contributions: PRC2 broadly constrains H3K27ac, whereas PRC1 more selectively shapes genome-wide H3K27ac redistribution and restricts H3K4me3 accumulation at bivalent promoters. Together, these findings identify staged active chromatin remodeling as an integral feature of perinatal oocyte development and reveal that Polycomb shapes chromatin state transitions as oocytes enter quiescence and become poised for future growth.

  PublisherOA PDFDOI

• KRAB zinc-finger proteins regulate endogenous retroviruses to sculpt germline transcriptomes and genome evolution

  Genome Research · 2025-03-01 · 6 citations

  articleOpen access

  As transposable elements (TEs) coevolved with the host genome, the host genome exploited TEs as functional regulatory elements of gene expression. Here we show that a subset of KRAB domain-containing zinc-finger proteins (KZFPs), which are highly expressed in mitotically dividing spermatogonia, repress the enhancer function of endogenous retroviruses (ERVs) and that the release from KZFP-mediated repression allows activation of ERV enhancers upon entry into meiosis. This regulatory feature is observed for independently evolved KZFPs and ERVs in mice and humans, suggesting evolutionary conservation in mammals. Further, we show that KZFP-targeted ERVs are underrepresented on the sex chromosomes in meiosis, suggesting that meiotic sex chromosome inactivation (MSCI) may antagonize the coevolution of KZFPs and ERVs in mammals. Our study uncovers a mechanism by which a subset of KZFPs regulate ERVs to sculpt germline transcriptomes. We propose that epigenetic programming during the transition from mitotic spermatogonia to meiotic spermatocytes facilitates the coevolution of KZFPs and TEs on autosomes and is antagonized by MSCI.

  PublisherOA PDFDOI

• Chromatin remodeler CHD4 establishes chromatin states required for ovarian reserve formation, maintenance and male germ cell survival

  Nucleic Acids Research · 2025-01-24 · 12 citations

  articleOpen access

  The ovarian reserve defines female reproductive lifespan, which in humans spans decades due to the maintenance of meiotic arrest in non-growing oocytes (NGOs) residing in primordial follicles. Unknown is how the chromatin state of NGOs is established to enable long-term maintenance of the ovarian reserve. Here, we show that a chromatin remodeler, CHD4, a member of the Nucleosome Remodeling and Deacetylase (NuRD) complex, establishes chromatin states required for formation and maintenance of the ovarian reserve. Conditional loss of CHD4 in perinatal mouse oocytes results in acute death of NGOs and depletion of the ovarian reserve. CHD4 establishes closed chromatin at regulatory elements of pro-apoptotic genes to prevent cell death and at specific genes required for meiotic prophase I to facilitate the transition from meiotic prophase I oocytes to meiotically-arrested NGOs. In male germ cells, CHD4 establishes closed chromatin at the regulatory elements of pro-apoptotic genes, allowing germ cell survival. These results demonstrate a role for CHD4 in defining a chromatin state that ensures germ cell survival, thereby enabling the long-term maintenance of both female and male germ cells.

  PublisherOA PDFDOI

• In vitro fertilization induces reproductive changes in male mouse offspring and has multigenerational effects

  JCI Insight · 2025-03-04 · 4 citations

  articleOpen access

  In vitro fertilization (IVF) is a noncoital method of conception used to treat human infertility. Although IVF is viewed as largely safe, it is associated with adverse outcomes in the fetus, placenta, and adult offspring. Because studies focusing on the effect of IVF on the male reproductive system are limited, we used a mouse model to assess the morphological and molecular effects of IVF on male offspring. We evaluated 3 developmental stages: 18.5-day fetuses and 12- and 39-week-old adults. Regardless of age, we observed changes in testicular-to-body weight ratios, serum testosterone levels, testicular morphology, gene expression, and DNA methylation. Also, sperm showed changes in morphology and DNA methylation. To assess multigenerational phenotypes, we mated IVF-conceived and naturally conceived males with wild-type females. Offspring from IVF males exhibited decreased fetal-to-placental weight ratios and changes in placenta gene expression and morphology regardless of sex. At 12 weeks of age, offspring showed higher body weights and differences in glucose, triglyceride, insulin, total cholesterol, HDL-C, and LDL/VLDL-C levels. Both sexes showed changes in gene expression in liver, testes, and ovaries and decreased global DNA methylation. Collectively, our findings demonstrate that male IVF offspring exhibit abnormal testicular and sperm morphology and molecular alterations with a multigenerational impact.

  PublisherOA PDFDOI

• An Epigenomic Roadmap Primes Non-Growing Oocytes for Maturation and Early Embryogenesis

  SSRN Electronic Journal · 2025-01-01 · 1 citations

  preprintOpen access
  PublisherDOI

• Newly Evolved Endogenous Retroviruses Prime the Ovarian Reserve for Activation

  Research Square · 2025-12-03

  preprintOpen access
  PublisherOA PDFDOI

• Newly Evolved Endogenous Retroviruses Prime the Ovarian Reserve for Activation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-12

  preprintOpen access

  Female mammals are born with a finite pool of non-growing oocytes (NGOs) housed in primordial follicles, which form the ovarian reserve that determines reproductive lifespan. Mechanisms underlying the reserve's long-term maintenance and subsequent follicular activation remain elusive. Using total RNA sequencing and de novo transcriptome assembly, we first captured the comprehensive oocyte transcriptome across perinatal oogenesis in mice. We show that NGOs establish accessible chromatin at gene regulatory elements-including promoters and enhancers-partly driven by newly evolved endogenous retroviruses (ERVs). In NGOs, epigenetic priming for follicular activation involves prior loading of transcription factors TCF3 and TCF12 and non-phosphorylated form of RNA polymerase II at these sites. This primed state is counteracted by repression via Polycomb Repressive Complex 1-mediated H2AK119 ubiquitylation. We propose that ERV-mediated epigenetic priming underlies the ovarian reserve's long-term maintenance and establishes a transcriptionally competent yet repressive configuration that enables rapid gene activation upon oocyte growth.

  PublisherDOI

• The SMARCA5–DMRT1 Pioneer Complex Establishes Epigenetic Priming to Direct Male Germline Development

  Research Square · 2025-10-08

  preprintOpen access
  PublisherOA PDFDOI

• In Vitro Fertilization Accelerates Female Reproductive Aging Through Early Ovarian Failure

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-14

  preprintOpen access

  Reproductive aging is characterized by the progressive decline of reproductive function, with broad implications for overall health and longevity. Environmental factors, including assisted reproductive technologies (ART), can accelerate reproductive aging by promoting premature ovarian failure in females. In vitro fertilization (IVF), though widely used and generally considered safe, is associated with lasting effects on offspring health. Using a mouse model that closely approximates human IVF, we demonstrate that IVF accelerates reproductive aging in female offspring by inducing premature ovarian failure. IVF-conceived females exhibit altered ovarian function, disrupted endocrine profiles, and transcriptomic and epigenetic changes consistent with premature reproductive decline. These findings reveal long-term consequences of IVF on female reproductive health and highlight the need to understand how early-life interventions influence reproductive longevity.

  PublisherOA PDFDOI

• The SMARCA5–DMRT1 Pioneer Complex Establishes Epigenetic Priming to Direct Male Germline Development

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-31

  preprintOpen access

  Abstract The establishment of cell type–specific chromatin landscapes is essential for cellular identity, but how these landscapes are generated remains poorly understood. Here, we demonstrate that the chromatin remodeler SMARCA5 establishes epigenetic priming that is required for retinoic acid (RA)–induced differentiation in the male germline. Germ cell–specific deletion of Smarca5 results in a complete loss of differentiating spermatogonia, phenocopying vitamin A-deficient mice that lack RA signaling. During the perinatal transition from prospermatogonia to undifferentiated spermatogonia, SMARCA5 is recruited to binding sites of the pioneer transcription factor DMRT1, which are located at distal putative enhancers and promoters of germline genes. The SMARCA5–DMRT1 pioneer complex establishes chromatin accessibility at these loci, generating poised enhancers and promoters that serve as RA receptor (RAR)–binding sites. Thus, SMARCA5 licenses transcriptional responses to RA that enable spermatogenic differentiation. Our findings uncover a mechanism linking pioneer factor activity to external signal responsiveness. Highlights SMARCA5 is required for spermatogonial differentiation The SMARCA5–DMRT1 pioneer complex establishes epigenetic priming for differentiation SMARCA5 remodels inaccessible DMRT1-binding sites to an accessible state SMARCA5 shapes chromatin states that enable retinoic acid responsiveness

  PublisherOA PDFDOI

Recent grants

• Gene Expression in the preimplantation Mouse Embryo

  NIH · $5.8M · 1987–2019

• Analytical Neurochemistry: Core D

  NIH · $12.7M · 2021

• NIH Grant U01HD044575

  NIH · $1.8M · 2009

• NIH Grant R37HD022681

  NIH · $2.9M · 2008

• Age and molecular mechanisms contributing to aneuploidy in oocytes

  NIH · $3.2M · 2008–2021

Frequent coauthors

• Paula Stein

  Research Triangle Park Foundation

  106 shared

• Sherri L. Andis

  Eli Lilly (United States)

  64 shared

• Gregory S. Kopf

  44 shared

• Michael A. Chirigos

  42 shared

• Peter J. Donovan

  University of California, Irvine

  40 shared

• Petr Svoboda

  Czech Academy of Sciences, Institute of Molecular Genetics

  39 shared

• A. Jeannine Lincoln

  Wright State University

  37 shared

• Steven I. Reed

  36 shared