Mis-expression of GATA6 re-programs cell fate during early hematopoiesis

Cindy Audiger; Yacine Laâbi; Junli Nie; Leonie Gibson; Julie Wilson-Annan; Phillip Brook-Carter; Andrew Kueh; Alan W Harris; Shalin Naik; Stephen L Nutt; Andreas Strasser; Jerry M Adams; Philippe Bouillet; Michaël Chopin

doi:10.1016/j.celrep.2024.114159

Mis-expression of GATA6 re-programs cell fate during early hematopoiesis

Cell Rep. 2024 Apr 26;43(5):114159. doi: 10.1016/j.celrep.2024.114159. Online ahead of print.

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne; Melbourne, VIC 3052, Australia.
² The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
³ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne; Melbourne, VIC 3052, Australia; Federation University Australia, Ballarat, VIC 3350, Australia.
⁴ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne; Melbourne, VIC 3052, Australia. Electronic address: nutt@wehi.edu.au.
⁵ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne; Melbourne, VIC 3052, Australia. Electronic address: strasser@wehi.edu.au.
⁶ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne; Melbourne, VIC 3052, Australia; Department of Biochemistry, Monash Biomedicine Discovery Institute, Monash University, 15 Innovation Walk, Clayton, VIC 3800, Australia.

PMID: 38676923
DOI: 10.1016/j.celrep.2024.114159

Abstract

The traditional view of hematopoiesis is that myeloid cells derive from a common myeloid progenitor (CMP), whereas all lymphoid cell populations, including B, T, and natural killer (NK) cells and possibly plasmacytoid dendritic cells (pDCs), arise from a common lymphoid progenitor (CLP). In Max41 transgenic mice, nearly all B cells seem to be diverted into the granulocyte lineage. Here, we show that these mice have an excess of myeloid progenitors, but their CLP compartment is ablated, and they have few pDCs. Nevertheless, T cell and NK cell development proceeds relatively normally. These hematopoietic abnormalities result from aberrant expression of Gata6 due to serendipitous insertion of the transgene enhancer (Eμ) in its proximity. Gata6 mis-expression in Max41 transgenic progenitors promoted the gene-regulatory networks that drive myelopoiesis through increasing expression of key transcription factors, including PU.1 and C/EBPa. Thus, mis-expression of a single key regulator like GATA6 can dramatically re-program multiple aspects of hematopoiesis.

Keywords: CP: Developmental biology; Eμ enhancer; GATA transcription factors; NK cells; T cells; common lymphoid progenitors; hematopoiesis; lineage deviation; plasmacytoid dendritic cells.