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Buenrostro, Jason

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Buenrostro

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Jason

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Buenrostro, Jason
Author's Publications: search.filters.isAuthorOfPublication.7e184c2a-8fa0-4bdb-b98e-fa707ef45e0a

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    Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence
    (Springer Science and Business Media LLC, 2021-03-31) Choi, Sekyu; Zhang, Bing; Ma, Sai; Gonzalez Celeiro, Meryem; Stein, Daniel; Jin, Xin; Kim, Seung Tea; Kang, Yuan-Lin; Besnard, Antoine; Rezza, Amelie; Grisanti, Laura; Buenrostro, Jason; Rendl, Michael; Nahrendorf, Matthias; Sahay, Amar; Hsu, Ya-chieh
    Chronic, sustained exposure to stressors can profoundly impact tissue homeostasis, although the mechanisms by which these changes occur are largely unknown. Here, we report the adrenal gland-derived stress hormone corticosterone (the rodent equivalent of cortisol) regulates hair follicle stem cell (HFSC) quiescence and hair growth in mice. Without systemic corticosterone, HFSCs enter substantially more rounds of the regeneration cycle throughout life. Conversely, under chronic stress, elevated corticosterone levels prolong HFSC quiescence and keep hair follicles in an extended resting phase. Mechanistically, corticosterone acts on dermal papilla (DP) to suppress the expression of a secreted factor, Growth Arrest Specific 6 (Gas6). Restoring Gas6 expression overcomes stress-induced inhibition of HFSC activation and hair growth. Our work identifies corticosterone as a systemic inhibitor of HFSC activity via its impact on the niche, and demonstrates that removal of such inhibition drives HFSCs into frequent regeneration cycles with no observable defects long-term.
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    chromVAR: Inferring transcription factor-associated accessibility from single-cell epigenomic data
    (2017) Schep, Alicia N.; Wu, Beijing; Buenrostro, Jason; Greenleaf, William J.
    Single cell ATAC-seq (scATAC) yields sparse data that makes application of conventional analysis approaches challenging. We developed chromVAR, an R package for analyzing sparse chromatin accessibility data by estimating gain or loss of accessibility within peaks sharing the same motif or annotation while controlling for technical biases. chromVAR enables accurate clustering of scATAC-seq profiles and enables characterization of known and de novo sequence motifs associated with variation in chromatin accessibility.
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    TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin
    (2017) Miller, Erik L.; Hargreaves, Diana C.; Kadoch, Cigall; Chang, Chiung-Ying; Calarco, Joseph P.; Hodges, Courtney; Buenrostro, Jason; Cui, Kairong; Greenleaf, William J.; Zhao, Keji; Crabtree, Gerald R.
    Resolution and formation of facultative heterochromatin is essential to development, reprogramming, and oncogenesis. The mechanisms underlying these changes are poorly understood due to the inability to study heterochromatin dynamics and structure in vivo. We devised an in vivo approach to investigate these mechanisms and found that topoisomerase II (TOP2), but not TOP1, synergizes with BAF (mSWI/SNF) ATP-dependent chromatin remodeling complexes genome-wide to resolve facultative heterochromatin to accessible chromatin independent of transcription, indicating that changes in DNA topology through (de-)catenation rather than release of torsional stress through swiveling is necessary for heterochromatin resolution. In turn, TOP2 and BAF cooperate to recruit pluripotency factors, explaining some of the instructive roles of BAF complexes. Unexpectedly, we found that TOP2, also plays a role in the reformation of facultative heterochromatin, suggesting that facultative heterochromatin and accessible chromatin exist at different states of catenation or other topologies, which may be critical to their structures.
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    Single-cell epigenomic variability reveals functional cancer heterogeneity
    (BioMed Central, 2017) Litzenburger, Ulrike M.; Buenrostro, Jason; Wu, Beijing; Shen, Ying; Sheffield, Nathan C.; Kathiria, Arwa; Greenleaf, William J.; Chang, Howard Y.
    Background: Cell-to-cell heterogeneity is a major driver of cancer evolution, progression, and emergence of drug resistance. Epigenomic variation at the single-cell level can rapidly create cancer heterogeneity but is difficult to detect and assess functionally. Results: We develop a strategy to bridge the gap between measurement and function in single-cell epigenomics. Using single-cell chromatin accessibility and RNA-seq data in K562 leukemic cells, we identify the cell surface marker CD24 as co-varying with chromatin accessibility changes linked to GATA transcription factors in single cells. Fluorescence-activated cell sorting of CD24 high versus low cells prospectively isolated GATA1 and GATA2 high versus low cells. GATA high versus low cells express differential gene regulatory networks, differential sensitivity to the drug imatinib mesylate, and differential self-renewal capacity. Lineage tracing experiments show that GATA/CD24hi cells have the capability to rapidly reconstitute the heterogeneity within the entire starting population, suggesting that GATA expression levels drive a phenotypically relevant source of epigenomic plasticity. Conclusion: Single-cell chromatin accessibility can guide prospective characterization of cancer heterogeneity. Epigenomic subpopulations in cancer impact drug sensitivity and the clonal dynamics of cancer evolution. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1133-7) contains supplementary material, which is available to authorized users.
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    Hyperactivation of Sympathetic Nerves Drives Depletion of Melanocyte Stem Cells
    (Springer Science and Business Media LLC, 2020-01-22) Zhang, Bing; Ma, Sai; Rachmin, Inbal; He, Megan; Baral, Pankaj; Choi, Sekyu; Gonçalves, William A.; Shwartz, Yulia; Fast, Eva; Su, Yiqun; Zon, Leonard I.; Regev, Aviv; Buenrostro, Jason; Cunha, Thiago M.; Chiu, Isaac M.; Fisher, David; Hsu, Ya-chieh
    Empirical and anecdotal evidence have associated stress with accelerated hair greying (formation of unpigmented hairs)1,2, but the scientific evidence linking the two is scant. Here, we report that acute stress leads to hair greying through fast depletion of melanocyte stem cells (MeSCs). Combining adrenalectomy, denervation, chemogenetics3,4, cell ablation, and MeSC-specific adrenergic receptor knockout, we found that stress-induced MeSC loss is independent of immune attack or adrenal stress hormones. Rather, hair greying results from activation of the sympathetic nerves that innervate the MeSC niche. Upon stress, sympathetic nerve activation leads to burst release of the neurotransmitter norepinephrine, which drives quiescent MeSCs into rapid proliferation, followed by differentiation, migration, and permanent depletion from the niche. Transient suppression of MeSC proliferation prevents stress-induced hair greying. Our studies demonstrate that acute stress-induced neuronal activity can drive rapid and permanent loss of somatic stem cells, and illustrate an example in which somatic stem cell maintenance is directly influenced by the overall physiological state of the organism.
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    Interrogation of human hematopoiesis at single-cell and single-variant resolution
    (Springer Science and Business Media LLC, 2019-03-11) Ulirsch, Jacob; Lareau, Caleb A.; Bao, Erik L.; Ludwig, Leif S.; Guo, Michael H.; Benner, Christian; Satpathy, Ansuman T.; Kartha, Vinay; Salem, Rany M.; Hirschhorn, Joel; Finucane, Hilary; Aryee, Martin; Buenrostro, Jason; Sankaran, Vijay
    Widespread linkage disequilibrium and incomplete annotation of cell-to-cell state variation represent substantial challenges to elucidating mechanisms of trait-associated genetic variation. Here, we perform genetic fine-mapping for blood cell traits in the UK Biobank to identify putative causal variants. These variants are enriched in genes encoding for proteins in trait-relevant biological pathways and in accessible chromatin of hematopoietic progenitors. For regulatory variants, we explore patterns of developmental enhancer activity, predict molecular mechanisms, and identify likely target genes. In several instances, we localize multiple independent variants to the same regulatory element or gene. We further observe that variants with pleiotropic effects preferentially act in common progenitor populations to direct the production of distinct lineages. Finally, we leverage fine-mapped variants in conjunction with continuous epigenomic annotations to identify trait-cell type enrichments within closely related populations and in single cells. Our study provides a comprehensive framework for single-variant and single-cell analyses of genetic associations.
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    Droplet-Based Combinatorial Indexing for Massive-Scale Single-Cell Chromatin Accessibility
    (Springer Science and Business Media LLC, 2019-06-24) Lareau, Caleb A.; Duarte, Fabiana; Chew, Jennifer G.; Kartha, Vinay; Burkett, Zach D.; Kohlway, Andrew S.; Pokholok, Dmitry; Aryee, Martin; Steemers, Frank J.; Lebofsky, Ronald; Buenrostro, Jason
    Recent technical advancements have facilitated the mapping of epigenomes at single-cell resolution; however, the throughput and quality of these methods have limited their widespread adoption. Here we describe a high-quality (105 nuclear fragments per cell) droplet-microfluidics-based method for single-cell profiling of chromatin accessibility. We use this approach, named ‘droplet single-cell assay for transposase-accessible chromatin using sequencing’ (dscATAC-seq), to assay 46,653 cells for the unbiased discovery of cell types and regulatory elements in adult mouse brain. We further increase the throughput of this platform by combining it with combinatorial indexing (dsciATAC-seq), enabling single-cell studies at a massive scale. We demonstrate the utility of this approach by measuring chromatin accessibility across 136,463 resting and stimulated human bone marrow-derived cells to reveal changes in the cis- and trans-regulatory landscape across cell types and under stimulatory conditions at single-cell resolution. Altogether, we describe a total of 510,123 single-cell profiles, demonstrating the scalability and flexibility of this droplet-based platform.
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    A microRNA expression and regulatory element activity atlas of the mouse immune system
    (Springer Science and Business Media LLC, 2021-06-07) Rose, Samuel A.; Wroblewska, Aleksandra; Dhainaut, Maxime; Yoshida, Hideyuki; Shaffer, Jonathan M.; Bektesevic, Anela; Ben-Zvi, Benjamin; Rhoads, Andrew; Kim, Edy Y.; Yu, Bingfei; Lavin, Yonit; Merad, Miriam; Buenrostro, Jason D.; Brown, Brian D.; Aguilar, Oscar; Allan, Rhys; Arakawa-Hoyt, Janice; Astarita, Jilian; Austen, K. Frank; Barrett, Nora; Baysoy, Alev; Benoist, Christophe; Buechler, Matthew; Buenrostro, Jason; Casanova, Maria Acebes; Choi, Kyunghee; Chowdhary, Kaitavjeet; Colonna, Marco; Crowl, Ty; Deng, Tianda; Desai, Jigar V.; Desland, Fiona; Ding, Jiarui; Dominguez, Claudia; Dwyer, Daniel; Frascoli, Michela; Gal-Oz, Shani; Goldrath, Ananda; Grieshaber-Bouyer, Ricardo; Jia, Baosen; Johanson, Tim; Jordan, Stefan; Kang, Joonsoo; Kapoor, Varun; Kenigsberg, Ephraim; Kim, Joel; Kim, Ki wook; Kiner, Evgeny; Kronenberg, Mitchell; Lanier, Lewis; Laplace, Catherine; Lareau, Caleb; Leader, Andrew; Lee, Jisu; Magen, Assaf; Maier, Barbara; Maslova, Alexandra; Mathis, Diane; McFarland, Adelle; Meunier, Etienne; Monach, Paul; Mostafavi, Sara; Muller, Soren; Muus, Christoph; Ner-Gaon, Hadas; Nguyen, Quyhn; Nigrovic, Peter A.; Niizuma, Kouta; Novakovsky, German; Nutt, Stephen; Omilusik, Kayla; Ortiz-Lopez, Adriana; Paynich, Mallory; Peng, Vincent; Potempa, Marc; Pradhan, Rachana; Quon, Sara; Ramirez, Ricardo; Ramanan, Deepshika; Randolph, Gwendalyn; Regev, Aviv; Seddu, Kumba; Shay, Tal; Shemesh, Avishai; Shyer, Justin; Smilie, Christopher; Spidale, Nick; Subramanian, Ayshwarya; Sylvia, Katelyn; Tellier, Julie; Turley, Shannon; Vijaykumar, Brinda; Wagers, Amy; Wang, Chendi; Wang, Peter L.; Yang, Liang; Yim, Aldrin
    microRNAs (miRNA) play an important role in immune system development and function, often participating in regulatory networks with the transcription factors that drive their expression. However, many of these relationships remain obscured because regulatory elements controlling miRNA expression in different immune cells remain largely uncharacterized. To address this, we analyzed miRNA expression and open chromatin regions (OCR) from >60 immune cell populations. This enabled us to establish maps of miRNA promoter and enhancer usage across the immune system. Unique miRNA signatures within different populations were associated with local chromatin accessibility changes, revealing putative regulatory elements for differentially expressed miRNAs. These maps suggest many miRNAs utilize multiple promoters to increase abundance, and also identified dominant and divergent miRNA regulatory elements between lineages and during immune cell development, as well as between closely clustered miRNAs. This study provides insight into the miRNA regulatory network of the immune system and is a resource for further discovery.