In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis

Lara-Astiaso, D. (David); Goñi-Salaverri, A. (Ainhoa); Mendieta-Esteban, J. (Julen); Narayan, N. (Nisha); Valle, C. (Cynthia) del; Gross, T. (Torsten); Giotopoulos, G. (George); Beinortas, T. (Tumas); Navarro-Alonso, M. (Mar); Aguado-Álvaro, L.P. (Laura Pilar); Zazpe, J. (Jon); Marchese, F.P. (Francesco P.); Torrea, N. (Natalia); Calvo, I.A. (Isabel A.); Lopez, C.K. (Cecile K.); Alignani, D. (Diego); López, A. (Andrés); Saez, B. (Borja); Taylor-King, J.P. (Jake P.); Prosper-Cardoso, F. (Felipe); Fortelny, N. (Nikolaus); Huntly, B.J.P. (Brian J. P.)

Keywords:

Área de Biomedicina
Cellular diferentiation
Chromatin structure
Bulk ex vivo
Single-cell in vivo CRISPR

Issue Date:

2023

Project:

886474 - ChRONAM-H - Chromatin Regulation Of Normal And Malignant Haematopoiesis
647685 - COMAL - COMAL:COhesin Mutations in Acute Leukemia: from modeling and mechanisms to novel therapeutics

ISSN:

1061-4036

Note:

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Citation:

Lara-Astiaso, D.; Goñi-Salaverri, A. (Ainhoa); Mendieta-Esteban, J. (Julen); et al. "In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis". Nature Genetics. 55 (9), 2023, 1542 - 1554

Abstract

Bulk ex vivo and single-cell in vivo CRISPR knockout screens are used to characterize 680 chromatin factors during mouse hematopoiesis, highlighting lineage-specific and normal and leukemia-specific functions. Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor-transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis.

URI:

https://hdl.handle.net/10171/67824

DOI:

10.1038/s41588-023-01471-2

Appears in Collections:

DA - CIMA - Terapias moleculares - Aptámeros - Artículos de revista

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