Dynamics of Chromatin Accessibility During Hematopoietic Stem Cell Differentiation Into Progressively Lineage-Committed Progeny

Author:

Martin Eric W1,Rodriguez y Baena Alessandra1,Reggiardo Roman E2,Worthington Atesh K1,Mattingly Connor S2,Poscablo Donna M1,Krietsch Jana2,McManus Michael T3,Carpenter Susan1,Kim Daniel H2,Forsberg E Camilla2ORCID

Affiliation:

1. Institute for the Biology of Stem Cells, Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz , Santa Cruz, CA , USA

2. Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz , Santa Cruz, CA , USA

3. Department of Microbiology and Immunology, Diabetes Center, W.M. Keck Center for Noncoding RNAs, University of California San Francisco , San Francisco, CA , USA

Abstract

Abstract Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Mapping the chromatin dynamics of functionally defined cell populations will shed mechanistic insight into 2 major, unanswered questions in stem cell biology: how does epigenetic identity contribute to a cell type’s lineage potential, and how do cascades of chromatin remodeling dictate ensuing fate decisions? Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors. Oligopotent progenitor populations operating between the HSCs and unipotent cells play essential roles in effecting hematopoietic homeostasis. To test the hypothesis that selective HSC-primed lineage-specific CREs remain accessible throughout differentiation, we used ATAC-seq to map the temporal dynamics of chromatin remodeling during progenitor differentiation. We observed epigenetic-driven clustering of oligopotent and unipotent progenitors into distinct erythromyeloid and lymphoid branches, with multipotent HSCs and MPPs associating with the erythromyeloid lineage. We mapped the dynamics of lineage-primed CREs throughout hematopoiesis and identified both unique and shared CREs as potential lineage reinforcement mechanisms at fate branch points. Additionally, quantification of genome-wide peak count and size revealed overall greater chromatin accessibility in HSCs, allowing us to identify HSC-unique peaks as putative regulators of self-renewal and multilineage potential. Finally, CRISPRi-mediated targeting of ATACseq-identified putative CREs in HSCs allowed us to demonstrate the functional role of selective CREs in lineage-specific gene expression. These findings provide insight into the regulation of stem cell multipotency and lineage commitment throughout hematopoiesis and serve as a resource to test functional drivers of hematopoietic lineage fate.

Funder

NIH

NHLBI

NIDDK

SCILL

San Jose State University

Genomic Sciences Graduate Training Program

NHGRI

Tobacco-Related Disease Research Program

American Heart Association Predoctoral Fellowship

Howard Hughes Medical Institute Gilliam

Baskin School of Engineering

Ken and Glory Levy Fund

University of California, Santa Cruz

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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