About

Roberto Bonasio, Ph.D., is a Professor of Cell and Developmental Biology at the University of Pennsylvania's Perelman School of Medicine. He is a core faculty member at the Penn Epigenetics Institute and a member of the Institute for Regenerative Medicine. His research focuses on the molecular mechanisms of epigenetic memory, noncoding RNAs, chromatin biochemistry, and the regulation of genes and behavior. Bonasio's work involves studying chromatin, epigenetics, and Polycomb group proteins, contributing to the understanding of gene regulation and epigenetic inheritance.

Research topics

• Biology
• Genetics
• Cell biology
• Computational biology
• Chemistry

Selected publications

• Socially regulated genes are spatially hyperconnected to enhancers in the ant brain

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-09

  articleOpen accessSenior authorCorresponding

  ABSTRACT Caste identity in Harpegnathos saltator ants remains plastic beyond development and throughout adulthood. Adult Harpegnathos workers can become dominant reproductives, known as “gamergates,” through a social caste transition that involves extensive transcriptional and cellular remodeling of the brain. To gain insight into the epigenetic regulation of this process, we generated comprehensive, caste-specific epigenomic atlases of the Harpegnathos brain, including chromatin accessibility, histone modifications, and 3D genome architecture. Using these data we refined the genome assembly, annotated enhancers, and linked them to target genes. We then identified candidate 3D-architectural factors, many of which were specifically upregulated in gamergate brains. Promoters of genes upregulated during the worker–gamergate transition formed an unusually high number of 3D chromatin contacts with their regulatory regions, and most of these contacts were already present in workers. We propose that the pre-existing hyper-connectivity of socially regulated genes is essential to adult brain plasticity and behavioral reprogramming.

  PublisherDOI

• Pseudouridine selects RNAs for extracellular transport

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-30

  preprintOpen accessSenior authorCorresponding

  RNAs move through the extracellular space to transmit information between cells, including mammalian neurons, yet how specific RNAs are channeled into these extracellular routes is unknown. Using genome-wide CRISPR screening, proteomics, and high-sensitivity transcriptomics in a neuronal cell line, we identify domesticated retroviral proteins and RNA-modifying enzymes that regulate RNA loading into and transportation via extracellular vesicles. We show that the pseudouridine synthase PUS1 is a key determinant of RNA trafficking, and that its catalytic product in RNA, pseudouridine, is both necessary and sufficient for extracellular RNA export. We further show that myosin light chain 6 (MYL6) is a pseudouridine-binding protein required for secretion of synthetic and endogenous RNAs. These findings reveal a biochemical code linking chemical RNA modification to extracellular transport, and establish a framework to study the function of extracellular RNAs in the nervous system and beyond.

  PublisherOA PDFDOI

• Chromatin landscape at cis-regulatory elements orchestrates cell fate decisions in early embryogenesis

  Nature Communications · 2025-03-27 · 17 citations

  articleOpen access

  The establishment of germ layers during early development is crucial for body formation. The Drosophila zygote serves as a model for investigating these transitions in relation to the chromatin landscape. However, the cellular heterogeneity of the blastoderm embryo poses a challenge for gaining mechanistic insights. Using 10× Multiome, we simultaneously analyzed the in vivo epigenomic and transcriptomic states of wild-type, E(z)-, and CBP-depleted embryos during zygotic genome activation at single-cell resolution. We found that pre-zygotic H3K27me3 safeguards tissue-specific gene expression by modulating cis-regulatory elements. Furthermore, we demonstrate that CBP is essential for cell fate specification functioning as a transcriptional activator by stabilizing transcriptional factors binding at key developmental genes. Surprisingly, while CBP depletion leads to transcriptional arrest, chromatin accessibility continues to progress independently through the retention of stalled RNA Polymerase II. Our study reveals fundamental principles of chromatin-mediated gene regulation essential for establishing and maintaining cellular identities during early embryogenesis.

  PublisherOA PDFDOI

• Neuropeptides specify and reprogram division of labor in the leafcutter ant Atta cephalotes

  Cell · 2025-06-11 · 9 citations

  articleOpen access
  PublisherOA PDFDOI

• Pooled scanning of protein variants identifies novel RNA-binding mutants

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-03

  preprintOpen accessSenior authorCorresponding

  Binding to RNA has been observed for an ever-increasing number of proteins, which often have other functions. The contributions of RNA binding to protein function are best discerned by studying separation-of-function mutants that hamper interaction with RNA without affecting other aspects of protein function. To design these mutants, we need precise knowledge of the residues that contribute to the affinity of the protein for its RNA ligands. Here, we present RBR-scan: a technology to simultaneously measure RNA-binding affinity of a large number of protein variants. We fused individual variants with unique peptide barcodes optimized for detection by mass spectrometry (MS), purified protein pools from single bacterial culture, and assayed proteins in parallel for RNA binding. Mutations in the MS2 coat protein known to impair RNA-binding were correctly identified, as well as a previously unreported mutant, which we validated with orthogonal biochemical methods. We used RBR-scan to discover novel RNA-binding mutants in the cancer-associated splicing regulator SRSF2. Together, our results demonstrate that RBR-scan is a powerful and scalable platform for linking RNA-binding affinity to protein sequence, offering a novel strategy to decode the functional consequences of protein-RNA interactions.

  PublisherOA PDFDOI

• IL-12 drives the differentiation of human T follicular regulatory cells

  Science Immunology · 2024-07-05 · 15 citations

  article

  T follicular regulatory (T fr ) cells can counteract the B cell helper activity of T follicular helper (T fh ) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (T reg ) cells into T fr cells is still missing. Herein, we report that low doses of the pro-T fh cytokine interleukin-12 (IL-12) drive the induction of a T fr cell program on activated human T reg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12–driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating T fr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of T fr cell differentiation in vivo and provides an approach for the in vitro generation of human T fr -like cells.

  PublisherDOI

• Neuropeptides specify and reprogram division of labor in the leafcutter ant <i>Atta cephalotes</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-08

  preprintOpen access

  ABSTRACT Social insects offer powerful models to investigate the mechanistic foundation of elaborate individual behaviors comprising a cooperative community. Workers of the leafcutter ant genus Atta provide an extreme example of behavioral segregation among many phenotypically distinct worker types. We utilize the complex worker system of Atta cephalotes to test the molecular underpinnings of behavioral programming and, in particular, the extent of plasticity to reprogramming. We identify specific neuropeptides as mediators of worker division of labor in A. cephalotes , finding two neuropeptides associated with characteristic behaviors of leafcutting and of brood care. Manipulation via genetic knockdown or by injection of these neuropeptides led to stark loss or gain of each behavior and to transcriptomic shifts in the predicted direction, that is, towards gene pathways expressed in the natural caste. We also compare specific A. cephalotes worker transcriptomes with those of orthologous workers of the eusocial mammal, the naked mole rat H. gaber , revealing global similarities between caste-biased expression and link to specific roles of our studied neuropeptides in ants. This work underscores the essential function of neuropeptides in establishing complex social behavior and a remarkable plasticity among individual behavioral types.

  PublisherOA PDFDOI

• A ligation-independent sequencing method reveals tRNA-derived RNAs with blocked 3′ termini

  Molecular Cell · 2024-08-02 · 17 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Long ant life span is maintained by a unique heat shock factor

  Genes & Development · 2023-05-01 · 8 citations

  articleOpen access

  Eusocial insect reproductive females show strikingly longer life spans than nonreproductive female workers despite high genetic similarity. In the ant Harpegnathos saltator ( Hsal ), workers can transition to reproductive “gamergates,” acquiring a fivefold prolonged life span by mechanisms that are poorly understood. We found that gamergates have elevated expression of heat shock response (HSR) genes in the absence of heat stress and enhanced survival with heat stress. This HSR gene elevation is driven in part by gamergate-specific up-regulation of the gene encoding a truncated form of a heat shock factor most similar to mammalian HSF2 (hsalHSF2). In workers, hsalHSF2 was bound to DNA only upon heat stress. In gamergates, hsalHSF2 bound to DNA even in the absence of heat stress and was localized to gamergate-biased HSR genes. Expression of hsalHSF2 in Drosophila melanogaster led to enhanced heat shock survival and extended life span in the absence of heat stress. Molecular characterization illuminated multiple parallels between long-lived flies and gamergates, underscoring the centrality of hsalHSF2 to extended ant life span. Hence, ant caste-specific heat stress resilience and extended longevity can be transferred to flies via hsalHSF2. These findings reinforce the critical role of proteostasis in health and aging and reveal novel mechanisms underlying facultative life span extension in ants.

  PublisherOA PDFDOI

• An efficient cloning method to expand vector and restriction site compatibility of Golden Gate Assembly

  Cell Reports Methods · 2023-08-01 · 15 citations

  articleOpen accessSenior authorCorresponding

  Golden Gate Assembly is an efficient and rapid cloning method but requires dedicated vectors. Here, we modified Golden Gate to expand its compatibility to a broader range of destination vectors while maintaining its strengths. Our Expanded Golden Gate (ExGG) assembly adds to the insert(s) type IIS restriction sites that generate protruding ends compatible with traditional type IIP sites on the recipient vector. The ligated product cannot be cleaved again, owing to a single-base change near the junction. This allows the reaction to proceed in a single tube without an intermediate purification step. ExGG can be used to introduce multiple fragments into a vector simultaneously, including shorter fragments (<100 bp) and fragments with shared sequences, which can be difficult to assemble with other fast cloning strategies. Thus, ExGG extends the convenience of Golden Gate to a much larger space of pre-existing vectors designed for conventional cloning.

  PublisherDOI

Recent grants

• Regulation of PRC2 by protein and RNA interactions during differentiation

  NIH · $1.3M · 2020–2024

• Genetically engineered ants to label and study neurons involved in social behavior

  NIH · $447k · 2021–2023

• Function and RNA-mediated regulation of SCMH1 in Polycomb repression

  NIH · $1.3M · 2018–2023

• Social control of lifespan regulation via glial plasticity in ants

  NIH · $1.7M · 2021–2026

• NIH Grant DP2MH107055

  NIH · $2.4M · 2019

Frequent coauthors

• Danny Reinberg

  New York University

  74 shared

• Janko Gospočić

  University Medical Center Freiburg

  30 shared

• Ulrich H. von Andrian

  Harvard University

  26 shared

• Emily J. Shields

  University of Freiburg

  23 shared

• Shelley L. Berger

  22 shared

• Benjamin A. García

  20 shared

• Lihong Sheng

  Fudan University

  19 shared

• Jean-Marc Gauguet

  Harvard University

  18 shared

Labs

• Roberto Bonasio LabPI

Education

• Ph.D., Immunology

  Harvard Medical School

  2006

• Laurea

  Università degli Studi di Milano

  2000