Ana Uzquiano, Amanda J Kedaigle, Martina Pigoni, Bruna Paulsen, Xian Adiconis, Kwanho Kim, Tyler Faits, Surya Nagaraja, Noelia Antón-Bolaños, Chiara Gerhardinger, Ashley Tucewicz, Evan Murray, Xin Jin, Jason Buenrostro, Fei Chen, Silvia Velasco, Aviv Regev, Joshua Z Levin, Paola Arlotta.2022.Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex.Cell.185(20):3770-3788.e27.DOI:10.1016/j.cell.2022.09.010
Ana Uzquiano, Amanda J Kedaigle, Martina Pigoni, Bruna Paulsen, Xian Adiconis, Kwanho Kim, Tyler Faits, Surya Nagaraja, Noelia Antón-Bolaños, Chiara Gerhardinger, Ashley Tucewicz, Evan Murray, Xin Jin, Jason Buenrostro, Fei Chen, Silvia Velasco, Aviv Regev, Joshua Z Levin, Paola Arlotta.2022.Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex.Cell.185(20):3770-3788.e27.DOI:10.1016/j.cell.2022.09.010
All Publications
2024
Schiroli G, Kartha V, Duarte FM, Kristiansen TA, Mayerhofer C, Shrestha R, Earl A, Hu Y, Tay T, Rhee C, Buenrostro JD, Scadden DT.2024.Cell of origin epigenetic priming determines susceptibility to Tet2 mutation.Nature communications.15(1):4325.Pubmed: 38773071DOI:10.1038/s41467-024-48508-6
Schiroli G, Kartha V, Duarte FM, Kristiansen TA, Mayerhofer C, Shrestha R, Earl A, Hu Y, Tay T, Rhee C, Buenrostro JD, Scadden DT.2024.Cell of origin epigenetic priming determines susceptibility to Tet2 mutation.Nature communications.15(1):4325.Pubmed: 38773071DOI:10.1038/s41467-024-48508-6
Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigate how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we find that the epigenetic features of clones at similar differentiation status are highly heterogeneous and functionally respond differently to Tet2 mutation. Cell differentiation stage also influences Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitizes cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.
Avagyan S, Weber MC, Ma S, Prasad M, Mannherz WP, Yang S, Buenrostro JD, Zon LI.2021.Single-cell ATAC-seq reveals GATA2-dependent priming defect in myeloid and a maturation bottleneck in lymphoid lineages.Blood advances.5(13):2673-2686.Pubmed: 34170284DOI:10.1182/bloodadvances.2020002992
Avagyan S, Weber MC, Ma S, Prasad M, Mannherz WP, Yang S, Buenrostro JD, Zon LI.2021.Single-cell ATAC-seq reveals GATA2-dependent priming defect in myeloid and a maturation bottleneck in lymphoid lineages.Blood advances.5(13):2673-2686.Pubmed: 34170284DOI:10.1182/bloodadvances.2020002992
Germline heterozygous mutations in GATA2 are associated with a syndrome characterized by cytopenias, atypical infections, and increased risk of hematologic malignancies. Here, we generated a zebrafish mutant of gata2b that recapitulated the myelomonocytopenia and B-cell lymphopenia of GATA2 deficiency syndrome. Using single-cell assay for transposase accessible chromatin with sequencing of marrow cells, we showed that loss of gata2b led to contrasting alterations in chromosome accessibility in early myeloid and lymphoid progenitors, associated with defects in gene expression. Within the myeloid lineage in gata2b mutant zebrafish, we identified an attenuated myeloid differentiation with reduced transcriptional priming and skewing away from the monocytic program. In contrast, in early lymphoid progenitors, gata2b loss led to accumulation of B-lymphoid transcription factor accessibility coupled with increased expression of the B-cell lineage-specification program. However, gata2b mutant zebrafish had incomplete B-cell lymphopoiesis with loss of lineage-specific transcription factor accessibility in differentiating B cells, in the context of aberrantly reduced oxidative metabolic pathways. Our results establish that transcriptional events in early progenitors driven by Gata2 are required to complete normal differentiation.
Zhang B, Ma S, Rachmin I, He M, Baral P, Choi S, Gonçalves WA, Shwartz Y, Fast EM, Su Y, Zon LI, Regev A, Buenrostro JD, Cunha TM, Chiu IM, Fisher DE, Hsu YC.2020.Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells.Nature.577(7792):676-681.Pubmed: 31969699DOI:10.1038/s41586-020-1935-3
Zhang B, Ma S, Rachmin I, He M, Baral P, Choi S, Gonçalves WA, Shwartz Y, Fast EM, Su Y, Zon LI, Regev A, Buenrostro JD, Cunha TM, Chiu IM, Fisher DE, Hsu YC.2020.Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells.Nature.577(7792):676-681.Pubmed: 31969699DOI:10.1038/s41586-020-1935-3
Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs), but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.
Mazumdar C, Shen Y, Xavy S, Zhao F, Reinisch A, Li R, Corces MR, Flynn RA, Buenrostro JD, Chan SM, Thomas D, Koenig JL, Hong WJ, Chang HY, Majeti R.2015.Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation.Cell stem cell.17(6):675-688.Pubmed: 26607380DOI:S1934-5909(15)00424-5
Mazumdar C, Shen Y, Xavy S, Zhao F, Reinisch A, Li R, Corces MR, Flynn RA, Buenrostro JD, Chan SM, Thomas D, Koenig JL, Hong WJ, Chang HY, Majeti R.2015.Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation.Cell stem cell.17(6):675-688.Pubmed: 26607380DOI:S1934-5909(15)00424-5
Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs. These effects are restricted to immature HSPC populations, where cohesin mutants show increased chromatin accessibility and likelihood of transcription factor binding site occupancy by HSPC regulators including ERG, GATA2, and RUNX1, as measured by ATAC-seq and ChIP-seq. Epistasis experiments show that silencing these transcription factors rescues the differentiation block caused by cohesin mutants. Together, these results show that mutant cohesins impair HSPC differentiation by controlling chromatin accessibility and transcription factor activity, possibly contributing to leukemic disease.