6533b870fe1ef96bd12d077c
RESEARCH PRODUCT
Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies.
Paolo GallipoliPaolo GallipoliHaiyang YunHaiyang YunDaniel SascaDaniel SascaDaniel SascaGeorge GiotopoulosGeorge GiotopoulosBerthold GöttgensBerthold GöttgensCameron S. OsborneRobert Kerrin HillsElli PapaemmanuilAnthony R. GreenAnthony R. GreenPeter J. CampbellMoritz GerstungBrian J. P. HuntlyBrian J. P. HuntlyNigel H. RussellJakub SzybinskiTheodore EvanTheodore EvanNicola K. WilsonNicola K. Wilsonsubject
0301 basic medicineMaleCohesin complexChromosomal Proteins Non-HistoneImmunologyGene DosageCell Cycle ProteinsBiologyRegulatory Sequences Nucleic AcidBiochemistryHistones03 medical and health sciences0302 clinical medicineNeoplasmshemic and lymphatic diseasesCell Line TumorBiomarkers TumorHumansTranscription factorRegulation of gene expressionHematopoietic stem cell homeostasisMyeloid NeoplasiaMyeloproliferative DisordersCohesinProto-Oncogene Proteins c-etsGene Expression Regulation LeukemicETS transcription factor familyMyeloid leukemiafood and beveragesCell BiologyHematologyHematopoietic Stem CellsCell biologyChromatinHematopoiesisRepressor Proteins030104 developmental biologyGene Expression Regulation030220 oncology & carcinogenesisMutationFemalesense organsbiological phenomena cell phenomena and immunityNeoplasm GradingBLOOD CommentaryProtein Bindingdescription
Cohesin complex disruption alters gene expression, and cohesin mutations are common in myeloid neoplasia, suggesting a critical role in hematopoiesis. Here, we explore cohesin dynamics and regulation of hematopoietic stem cell homeostasis and differentiation. Cohesin binding increases at active regulatory elements only during erythroid differentiation. Prior binding of the repressive Ets transcription factor Etv6 predicts cohesin binding at these elements and Etv6 interacts with cohesin at chromatin. Depletion of cohesin severely impairs erythroid differentiation, particularly at Etv6-prebound loci, but augments self-renewal programs. Together with corroborative findings in acute myeloid leukemia and myelodysplastic syndrome patient samples, these data suggest cohesin-mediated alleviation of Etv6 repression is required for dynamic expression at critical erythroid genes during differentiation and how this may be perturbed in myeloid malignancies.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-12-12 | Blood |