TY - JOUR
T1 - Mis-expression of GATA6 re-programs cell fate during early hematopoiesis
AU - Audiger, Cindy
AU - Laâbi, Yacine
AU - Nie, Junli
AU - Gibson, Leonie
AU - Wilson-Annan, Julie
AU - Brook-Carter, Phillip
AU - Kueh, Andrew
AU - Harris, Alan W.
AU - Naik, Shalin
AU - Nutt, Stephen L.
AU - Strasser, Andreas
AU - Adams, Jerry M.
AU - Bouillet, Philippe
AU - Chopin, Michaël
N1 - Funding Information:
We thank J. Martin, L. Spencer, T. Kapitelli, and G. Siciliano for animal care and expertise; Dr. M. Herold, J. Stanley, L. Tai, F. Watson, and A. Morcom for the generation of CRISPR genetically altered mice; Dr. C. de Graaf for gene signature lists; and Drs. N. Jenkins, N. Copeland, G. Lindeman, A. Ng, T. Johanson, W. Alexander, and S. Chappaz for insightful discussions. This work was supported by the Australian NHMRC (program grant 461221, Research Fellowships 1042629, and 1196235, project grant 1127885, investigator grant 2026084, and Ideas grant 2000461), the Arthritis Australia Zimmer fellowship, and infrastructure support from the NHMRC (IRISS) and the Victorian State Government (OIS). Generation of genetically engineered mice used in this study was supported by the Australian Phenomics Network (APN) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. Conceptualization, J.M.A. A.W.H. P.B. and M.C.; methodology, C.A. Y.L. J.N. A.K. and M.C.; investigation, C.A. Y.L. J.N. L.G. J.W.-A. P.B.-C. A.K. S.L.N. and M.C.; funding acquisition, J.M.A. P.B. S.N. S.L.N. and M.C.; supervision, J.M.A. P.B. S.L.N. and M.C.; writing \u2013 original draft, P.B. and M.C.; writing \u2013 review and editing, P.B. M.C. J.M.A. S.L.N. and A.S. The authors declare no competing interests.
Publisher Copyright:
© 2024 The Author(s)
PY - 2024/5/28
Y1 - 2024/5/28
N2 - 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.
AB - 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.
KW - common lymphoid progenitors
KW - CP: Developmental biology
KW - Eμ enhancer
KW - GATA transcription factors
KW - hematopoiesis
KW - lineage deviation
KW - NK cells
KW - plasmacytoid dendritic cells
KW - T cells
UR - https://www.scopus.com/pages/publications/85191150221
U2 - 10.1016/j.celrep.2024.114159
DO - 10.1016/j.celrep.2024.114159
M3 - Article
C2 - 38676923
AN - SCOPUS:85191150221
SN - 2211-1247
VL - 43
JO - Cell Reports
JF - Cell Reports
IS - 5
M1 - 114159
ER -