About

Michael L. Atchison, PhD, is a faculty member in the Department of Biomedical Sciences at the Perelman School of Medicine, University of Pennsylvania. His research focuses on the molecular mechanisms responsible for transcriptional regulation, epigenetic processes, and the control of B and T cell lineage development. His laboratory studies the function of transcription factor YY1 in controlling hematopoietic lineage commitment via long-range chromatin interactions coupled with repressive histone modifications. Dr. Atchison's work includes investigating how YY1 is recruited early in lineage development to key locations in the genome by pioneer transcription factors, forming and stabilizing long-distance DNA interactions at lineage-appropriate genes, and recruiting the Polycomb Group complex to generate H2K27me3 modifications at alternative lineage genes. His research aims to define universal mechanisms for lineage commitment that can be manipulated both experimentally and therapeutically. His studies also explore the molecular and functional fidelities of lineage cells derived from YY1-null pro-B cells, examining the molecular features and cellular functions of T lineage cells that develop from these progenitors. He is involved in addressing key questions about the mechanisms of B lineage commitment, the control of chromatin structures regulating lineage decisions, and the extent of hematopoietic plasticity caused by YY1 knockout. His work employs various genomic and cellular approaches, including Hi-C, ChIP-seq, ATAC-seq, RNA-seq, and proteomics, to understand the molecular underpinnings of hematopoietic development and lineage plasticity.

Research topics

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

Selected publications

• YY1-Mediated Polycomb Group Function Safeguards Hematopoietic Stem Cells from Premature Aging

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-29

  article

  Abstract Hematopoietic stem cells (HSCs) undergo functional decline with age, characterized by myeloid-biased differentiation, loss of quiescence, and altered metabolic homeostasis. The molecular mechanisms driving these changes remain incompletely understood. Yin Yang 1 (YY1) is a multifunctional transcription factor and mammalian Polycomb group (PcG) protein that recruits PcG complexes to specific genomic loci via its 26–amino acid REPO (Recruitment of Polycomb) domain. To define the role of YY1 PcG function in adult HSCs, we generated a conditional YY1 REPO domain knockout mouse model ( Yy1 −/ΔREPO ). Deletion of the REPO domain led to premature HSC aging, with expansion of immunophenotypic HSCs but loss of long-term self-renewal capacity. Yy1 −/ΔREPO HSCs exhibited myeloid-biased output, expansion of myeloid-primed multipotent progenitors, increased myeloid colony formation, and an elevated myeloid-to-lymphoid ratio in peripheral blood. These cells displayed reduced quiescence, elevated reactive oxygen species, increased mitochondrial oxidative capacity, and enhanced β-galactosidase activity—hallmarks of cellular aging. RNA-seq demonstrated dysregulation of gene networks governing HSC metabolism. Together, these findings establish YY1 PcG activity as a key epigenetic mechanism that preserves metabolic quiescence, sustains long-term self-renewal, and delays HSC aging. Our studies reveal a fundamental PcG-dependent epigenetic mechanism that dictate cell fate decisions and function decline during HSC aging.

  PublisherDOI

• Chromatin factor YY1 controls fetal hematopoietic stem cell migration and engraftment in mice

  Journal of Clinical Investigation · 2025-07-29 · 3 citations

  articleOpen access

  The fetal liver is the primary site of hematopoietic stem cell (HSC) generation during embryonic development. However, the molecular mechanisms governing the transition of hematopoiesis from the fetal liver to the BM remain incompletely understood. Here, we identify the mammalian Polycomb Group protein Yin Yang 1 (YY1) as a key regulator of this developmental transition. Conditional deletion of Yy1 in the hematopoietic system during fetal development results in neonatal lethality and depletion of the fetal HSC pool. YY1-deficient fetal HSCs exhibit impaired migration and fail to engraft in the adult BM, thereby losing their ability to reconstitute hematopoiesis. Transcriptomic analysis reveals that Yy1 KO disrupts genetic networks controlling cell motility and adhesion in fetal hematopoietic stem and progenitor cells (HSPCs). Notably, YY1 does not directly bind the promoters of most dysregulated genes. Instead, it modulates chromatin accessibility at regulatory loci, orchestrating broader epigenetic programs essential for HSPC migration and adhesion. Together, these findings establish YY1 as a critical epigenetic regulator of fetal HSC function and provide a mechanistic framework to further decipher how temporal epigenomic configurations determine HSC fetal-to-adult transition during development.

  PublisherOA PDFDOI

• YY1 knockout in pro-B cells impairs lineage commitment, enabling unusual hematopoietic lineage plasticity

  Genes & Development · 2024-09-01 · 5 citations

  articleOpen accessSenior author

  During B-cell development, cells progress through multiple developmental stages, with the pro-B-cell stage defining commitment to the B-cell lineage. YY1 is a ubiquitous transcription factor that is capable of both activation and repression functions. We found here that knockout of YY1 at the pro-B-cell stage eliminates B lineage commitment. YY1 knockout pro-B cells can generate T lineage cells in vitro using the OP9-DL4 feeder system and in vivo after injection into sublethally irradiated Rag1 −/− mice. These T lineage-like cells lose their B lineage transcript profile and gain a T-cell lineage profile. Single-cell RNA-seq experiments showed that as YY1 knockout pro-B cells transition into T lineage cells in vitro, various cell clusters adopt transcript profiles representing a multiplicity of hematopoietic lineages, indicating unusual lineage plasticity. In addition, YY1 KO pro-B cells in vivo can give rise to other hematopoietic lineages in vivo. Evaluation of RNA-seq, scRNA-seq, ChIP-seq, and scATAC-seq data indicates that YY1 controls numerous chromatin-modifying proteins leading to increased accessibility of alternative lineage genes in YY1 knockout pro-B cells. Given the ubiquitous nature of YY1 and its dual activation and repression functions, YY1 may regulate commitment in multiple cell lineages.

  PublisherDOI

• Unusual lineage plasticity revealed by YY1 knockout in pro-B cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-27

  preprintOpen accessSenior authorCorresponding

  Abstract During B cell development, cells progress through multiple developmental stages with the pro-B cell stage defining commitment to the B cell lineage. YY1 is a ubiquitous transcription factor that is capable of both activation and repression functions. We find here that knockout of YY1 at the pro-B cell stage eliminates B lineage commitment. YY1 knockout pro-B cells can generate T lineage cells in vitro using the OP9- DL4 feeder system, as well as in vivo after injection into sub-lethally irradiated Rag1 -/- mice. These T lineage-like cells lose their B lineage transcript profile and gain a T cell lineage profile. Single cell-RNA-seq experiments showed that as YY1 knockout pro-B cells transition into T lineage cells, various cell clusters adopt transcript profiles representing a multiplicity of hematopoietic lineages indicating unusual lineage plasticity. Given the ubiquitous nature of YY1 and its dual activation and repression functions, YY1 likely regulates commitment in multiple cell lineages.

  PublisherOA PDFDOI

• YY1-Mediated PcG Regulation Dictates Hematopoietic Stem Cell Fate

  Blood · 2024-11-05 · 1 citations

  articleOpen access

  Hematopoietic stem cells (HSCs) are undifferentiated, pluripotent cells that can either self-renew or differentiate into any of the mature lineage-specific cells in adult blood. Physiological aging and hematological malignancies in humans and mice are associated with dysregulation of the epigenetic landscape leading to biased HSC differentiation. The mechanisms that maintain normal HSC differentiation and balanced lineage output are incompletely understood. Mammalian Polycomb Group (PcG) proteins are negative regulators of gene expression that bind as large complexes to chromatin regulatory regions. However, many questions remain unanswered regarding mechanisms underlying the locus-specific targeting of PcG complexes. Yin Yang 1 (YY1) is unique among mammalian PcG proteins as it recruits other PcG proteins to its target genes and coordinates extensive long-range chromatin interactions (LRCIs) in upstream promoter/enhancer regions to activate/repress transcription of these genes. We have mapped the PcG function of YY1 to a small motif (aa 201-226), known as the Recruitment of Polycomb (REPO) domain, and demonstrated that it is essential to recruit other PcG proteins, stably repress transcription and initiate chromatin remodeling in YY1 target genes. Our previous work established a new paradigm in the regulation of lymphopoiesis by discovering that the YY1 REPO domain is required for Vκ gene rearrangement in pro-B cells and early T-cell survival. These results suggest that YY1 may orchestrate other PcG proteins in hematopoiesis through its PcG domain, which would have broad implications for YY1 as a coordinator of higher-order chromatin remodeling during HSC differentiation. Our prior studies in mice show that YY1-deficient HSCs fail to self-renew, do not remain quiescent, and have disrupted HSC metabolic regulatory networks. Ectopic expression of the YY1 PcG domain-deleted mutant (YY1ΔREPO) promotes the development of myeloid cells, indicating a requirement for YY1 PcG function to maintain HSC lineage balance. We further generated a YY1ΔREPO mouse model (Yy1-/ΔREPO) using CRISPR-Cas9 gene editing. Deletion of the YY1 PcG function/REPO domain leads to expansion of CD61high phenotypic LT-HSCs, but with reduced capacity to long-term self-renew. Yy1-/ΔREPO HSCs displayreduced quiescence, higher intracellular reactive oxygen species and increased mitochondrial membrane potential. The YY1 PcG domain deletion leads to HSC myeloid skew with expansion of myeloid primed multipotent progenitors (MPPs), increased myeloid specific colonies (CFU-G, M, GM) and increased myeloid / lymphoid ratio in peripheral blood. Thus, YY1ΔREPO mice show hallmarks of aging-related changes in hematopoiesis. In addition, N-terminally truncated YY1 201-414, which is sufficient for YY1-mediated long-range chromatin interactions, rescued hematologic defects in Yy1-/- mice, when expressed via the endogenous ROSA 26 promoter. These results support a model in which YY1 PcG function in chromatin structural regulation is essential for balanced HSC differentiation. CUT&Tag analysis in hematopoietic stem progenitor cells support that YY1 co-occupies with essential chromatin structural regulator cohesin at a large cohort of promoters genome-wide. Gene promoters with YY1-dependent occupancy are enriched in HSC metabolic process. Consistently, RNA-seq analysis of Yy1-/ΔREPO HSCs revealed the genetic network governing HSC metabolism were deregulated with down regulation of Hif1α and Hif3α indicating essential role of YY1 PcG function in HSC metabolism and differentiation. Our study supports that YY1 PcG function/chromatin remodeling is critical for HSC metabolism and differentiation. Disruption of YY1 mediated PcG function leads to acceleration of HSC aging.Our studies have elucidated innovative mechanisms and pathways by which epigenetic mechanisms dictate cell fate decisions during normal hematopoiesis.

  PublisherOA PDFDOI

• Multiple lineage-specific epigenetic landscapes at the antigen receptor loci

  Aging Research · 2023-07-01

  articleOpen accessSenior author

  Antigen receptors (AgRs) expressed on B and T cells provide the adaptive immune system with ability to detect numerous foreign antigens. Epigenetic features of B cell receptor (BCR) and T cell receptor (TCR) genes were previously studied in lymphocytes, but little is known about their epigenetic features in other cells. Here, we explored histone modifications and transcription markers at the BCR and TCR loci in lymphocytes (pro-B, DP T cells, and mature CD4⁺ T cells), compared to embryonic stem (ES) cells and neurons. In B cells, the BCR loci exhibited active histone modifications and transcriptional markers indicative of active loci. Similar results were observed at the TCR loci in T cells. All loci were largely inactive in neurons. Surprisingly, in ES cells all AgR loci displayed a high degree of active histone modifications and markers of active transcription. Locations of these active histone modifications in ES cells were largely distinct from those in pro-B cells, and co-localized at numerous binding locations for transcription factors Oct4, Sox2, and Nanog. ES and pro-B cells also showed distinct binding patterns for the ubiquitous transcription factor YY1 and chromatin remodeler Brg1. On the contrary, there were many overlapping CCCTC-binding factor (CTCF) binding patterns when comparing ES cells, pro-B cells, and neurons. Our study identifies epigenetic features in ES cells and lymphocytes that may be related to ES cell pluripotency and lymphocyte tissue-specific activation at the AgR loci.

  PublisherOA PDFDOI

• YY1 control of mitochondrial‐related genes does not account for regulation of immunoglobulin class switch recombination in mice

  European Journal of Immunology · 2020-02-24 · 12 citations

  articleOpen accessSenior authorCorresponding

  Immunoglobulin class switch recombination (CSR) occurs in activated B cells with increased mitochondrial mass and membrane potential. Transcription factor Yin Yang 1 (YY1) is critical for CSR and for formation of the DNA loops involved in this process. We therefore sought to determine if YY1 knockout impacts mitochondrial gene expression and mitochondrial function in murine splenic B cells, providing a potential mechanism for regulating CSR. We identified numerous genes in splenic B cells differentially regulated when cells are induced to undergo CSR. YY1 conditional knockout caused differential expression of 1129 genes, with 59 being mitochondrial-related genes. ChIP-seq analyses showed YY1 was directly bound to nearly half of these mitochondrial-related genes. Surprisingly, at the time when YY1 knockout dramatically reduces DNA loop formation and CSR, mitochondrial mass and membrane potential were not significantly impacted, nor was there a significant change in mitochondrial oxygen consumption, extracellular acidification rate, or mitochondrial complex I or IV activities. Our results indicate that YY1 regulates numerous mitochondrial-related genes in splenic B cells, but this does not account for the impact of YY1 on CSR or long-distance DNA loop formation.

  PublisherOA PDFDOI

• Altered 3D chromatin structure permits inversional recombination at the <i>IgH</i> locus

  Science Advances · 2020-08-14 · 22 citations

  articleOpen access

  Different mechanisms govern the first and second steps of IgH gene recombination.

  PublisherOA PDFDOI

• Interplay of YY1 and CtBP in the recruitment of PcG complexes to DNA.

  The FASEB Journal · 2020-04-01

  article

  Recruitment of Polycomb Group (PcG) proteins to DNA is vital for normal development. PcG proteins regulate expression of homeotic genes that are essential for axial body patterning during development. Earlier work showed that YAF2 is responsible for PcG recruitment to DNA, which is mediated by YY1 DNA binding. Our goal is to understand the role of CtBP, YAF2 and YY1 in context of recruitment of Polycomb complexes to DNA. Using a co‐immunoprecipitation (CoIP) approach, different protein‐protein interactions are studied using protein‐specific antibodies. This approach will allow us to recognize binding interactions between specific proteins. Moreover, our preliminary results show that CtBP might interact directly with the C‐terminal end of YY1 to recruit PcG proteins. CtBP represses transcription in a histone deacetylase‐dependent or ‐independent manner, depending on the promoter context. Based on this information, we are investigating the modulation of transcriptional activity of YY1 upon interaction with CtBP using luciferase‐based assays. In conclusion, our studies will provide information regarding the interplay between CtBP, YAF2, and YY1 and their overall relationship in recruitment of PcG proteins to DNA. Support or Funding Information Start up funds from Penn State Brandywine

  PublisherDOI

• Author response for "YY1 Control of Mitochondrial-Related Genes does not Account for Regulation of Immunoglobulin Class Switch Recombination in mice"

  2019-12-30

  peer-reviewSenior author
  PublisherDOI

Recent grants

• The role of YY1 in constitutive and inducible DNA loop formation

  NIH · $1.2M · 2014–2019

• YY1-dependent chromatin structure stabilization of B lineage commitment

  NIH · $2.5M · 2021–2026

• NIH Grant R01HD042011

  NIH · $1.8M · 2007

• NIH Grant R01GM082841

  NIH · $1.2M · 2015

• NIH Grant R01GM071830

  NIH · $1.3M · 2011

Frequent coauthors

• F Sanderson

  25 shared

• Ronald E. Baynes

  North Carolina State University

  25 shared

• J. A. Crombie

  Imperial College London

  25 shared

• Lyon Playfair

  25 shared

• Alan W. Baird

  University College Dublin

  25 shared

• Benjamin Baker

  Peter MacCallum Cancer Centre

  25 shared

• Treas villiamson

  University of Aberdeen

  25 shared

• J. Matthews

  25 shared

Labs

• Atchison LaboratoryPI