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Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis [ATAC-Seq]

ABSTRACT: Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation, however cohesin-mutant leukemias do not show genomic instability. We hypothesized reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Bi-allelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation, and revealed an absolute requirement for cohesin in hematopoietic stem cell function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose-dependency for cohesin in regulating chromatin structure and hematopoietic stem cell function. ATAC-seq in murine c-kit+ cells for the following genotypes: Smc3 fl/+, Smc3 del/+, Flt3-ITD, Smc3 fl/del Flt3-ITD

ORGANISM(S): Mus musculus

SUBMITTER: James Bradner

PROVIDER: E-GEOD-73215 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis [RNA-Seq]

Project description:Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation, however cohesin-mutant leukemias do not show genomic instability. We hypothesized reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Bi-allelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation, and revealed an absolute requirement for cohesin in hematopoietic stem cell function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose-dependency for cohesin in regulating chromatin structure and hematopoietic stem cell function.

2015-10-01 | GSE73216 | GEO

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis [ATAC-Seq]

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Chronic growth factor signaling in Acute Myeloid Leukemia is connected to a specific chromatin signature [DNAse-Seq]

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Project description:During the germinal center (GC) reaction, B-cells undergo extensive redistribution of cohesin complex and 3D re-organization of their genomes. Yet, the significance of cohesin and architectural programming in the humoral immune response is unknown. Herein we report that conditional homozygous deletion of cohesin subunit Smc3 abrogated GC formation, yet in marked contrast, Smc3 haploinsufficiency induced GC hyperplasia, skewing of GC polarity and impaired plasma cell differentiation. Transcriptional and architectural profiling revealed defects in GC terminal differentiation programs controlled by lymphoma epigenetic tumor suppressors Tet2 and Kmt2d, and failure of Smc3+/- GC B-cells to switch from B-cell to plasma cell lineage factors. There was also impaired connectivity of gene regulatory elements controlling tumor suppressor genes, and accordingly Smc3 haploinsufficiency accelerated lymphomagenesis in mice with constitutive Bcl6 expression. Collectively, our data indicate a dose dependent function for cohesin in humoral immunity to facilitate the B-cell to plasma cell lineage switch, while restricting their malignant transformation.

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