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Hock, Hanno

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Hock

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Hanno

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Hock, Hanno

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2012 - 20193

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Author's Publications: search.filters.isAuthorOfPublication.6475499f-23ad-4f9e-9d67-9e391644dfd5

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    Distinct, strict requirements for Gfi-1b in adult bone marrow red cell and platelet generation
    (The Rockefeller University Press, 2014) Foudi, Adlen; Kramer, Danny; Qin, Jinzhong; Ye, Denise; Behlich, Anna-Sophie; Mordecai, Scott; Preffer, Frederic; Amzallag, Arnaud; Ramaswamy, Sridhar; Hochedlinger, Konrad; Orkin, Stuart; Hock, Hanno
    The zinc finger transcriptional repressor Gfi-1b is essential for erythroid and megakaryocytic development in the embryo. Its roles in the maintenance of bone marrow erythropoiesis and thrombopoiesis have not been defined. We investigated Gfi-1b’s adult functions using a loxP-flanked Gfi-1b allele in combination with a novel doxycycline-inducible Cre transgene that efficiently mediates recombination in the bone marrow. We reveal strict, lineage-intrinsic requirements for continuous adult Gfi-1b expression at two distinct critical stages of erythropoiesis and megakaryopoiesis. Induced disruption of Gfi-1b was lethal within 3 wk with severely reduced hemoglobin levels and platelet counts. The erythroid lineage was arrested early in bipotential progenitors, which did not give rise to mature erythroid cells in vitro or in vivo. Yet Gfi-1b−/− progenitors had initiated the erythroid program as they expressed many lineage-restricted genes, including Klf1/Eklf and Erythropoietin receptor. In contrast, the megakaryocytic lineage developed beyond the progenitor stage in Gfi-1b’s absence and was arrested at the promegakaryocyte stage, after nuclear polyploidization, but before cytoplasmic maturation. Genome-wide analyses revealed that Gfi-1b directly regulates a wide spectrum of megakaryocytic and erythroid genes, predominantly repressing their expression. Together our study establishes Gfi-1b as a master transcriptional repressor of adult erythropoiesis and thrombopoiesis.
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    The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes
    (The Rockefeller University Press, 2012) Mou, Fan; Praskova, Maria; Xia, Fan; Van Buren, Denille; Hock, Hanno; Avruch, Joseph; Zhou, Dawang
    The Mst1 kinase is an important regulator of murine T cell adhesion, migration, proliferation, and apoptosis. In this study, we analyze mice lacking both Mst1 and Mst2 in hematopoietic cells. Compared with wild-type mice, these double knockout (DKO) mice exhibit a severe reduction in the number of mature T cells in the circulation and in secondary lymphoid organs (SLOs). CD4+CD8− and CD4−CD8+ single-positive (SP) thymocytes in DKO mice resemble mature T cells of wild-type mice but undergo excessive apoptosis, and their egress from the thymus is reduced by >90%. Even when placed directly in the circulation, DKO SP thymocytes failed to enter SLOs. In SP thymocytes, deficiency of Mst1 and Mst2 abolished sphingosine-1 phosphate– and CCL21-induced Mob1 phosphorylation, Rac1 and RhoA GTP charging, and subsequent cell migration. When phosphorylated by Mst1 or Mst2, Mob1 binds and activates the Rac1 guanyl nucleotide exchanger Dock8, which is abundant in the thymus. Thus, the Mst1 and Mst2 kinases control Rho GTPase activation and the migratory responses of SP thymocytes.
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    Inducible Histone K-to-M Mutations are Dynamic Tools to Probe the Physiological Role of Site-Specific Histone Methylation In Vitro and In Vivo
    (Springer Science and Business Media LLC, 2019-10-28) Brumbaugh, Justin; Kim, Ik Soo; Ji, Fei; Huebner, Aaron; Di Stefano, Bruno; Schwarz, Benjamin A.; Charlton, Jocelyn; Coffey, Amy; Choi, Jiho; Walsh, Ryan M.; Schindler, Jeffrey W.; Anselmo, Anthony; Meissner, Alexander; Sadreyev, Ruslan; Bernstein, Bradley; Hock, Hanno; Hochedlinger, Konrad
    Development and differentiation are associated with profound changes to histone modifications, yet their in vivo function remains incompletely understood. Here, we generated mouse models expressing inducible histone H3 lysine-to-methionine mutants, which globally inhibit methylation at specific sites. Mice expressing H3K36M developed severe anemia with arrested erythropoiesis, a marked hematopoietic stem cell defect, and rapid lethality. By contrast, mice expressing H3K9M survived up to a year and showed expansion of multipotent progenitors, aberrant lymphopoiesis and thrombocytosis. Additionally, some H3K9M mice succumbed to aggressive T cell leukemia/lymphoma while H3K36M mutants exhibited differentiation defects in testis and intestine. Mechanistically, H3K36M and H3K9M reduced H3K36 and H3K9 trimethylation patterns genome-wide and altered chromatin accessibility and gene expression landscapes. Strikingly, discontinuation of transgene expression largely restored differentiation programs. Our work shows that individual chromatin modifications are required at several specific stages of differentiation and introduces powerful tools to interrogate their roles in vivo.