Abundant binary promoter switches in lineage-determining transcription factors indicate a digital component of cell fate determination

Hongchuan Li; Md Ahasanur Rahman; Michael Ruesch; Caprice D Eisele; Erik M Anderson; Paul W Wright; Jennie Cao; Shashikala Ratnayake; Qingrong Chen; Chunhua Yan; Daoud Meerzaman; Roshini S Abraham; Aharon G Freud; Stephen K Anderson

doi:10.1016/j.celrep.2023.113454

Abundant binary promoter switches in lineage-determining transcription factors indicate a digital component of cell fate determination

Cell Rep. 2023 Nov 28;42(11):113454. doi: 10.1016/j.celrep.2023.113454. Epub 2023 Nov 16.

Authors

Affiliations

¹ Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
² Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
³ Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Medical Scientist Training Program, The Ohio State University, Columbus, OH 43210, USA.
⁴ Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
⁵ Cancer Genomics and Bioinformatics Branch, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, MD 20892, USA.
⁶ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43210, USA; Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.
⁷ Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.
⁸ Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Electronic address: andersonst@nih.gov.

Abstract

Previous studies of the murine Ly49 and human KIR gene clusters implicated competing sense and antisense promoters in the control of variegated gene expression. In the current study, an examination of transcription factor genes defines an abundance of convergent and divergent sense/antisense promoter pairs, suggesting that competing promoters may control cell fate determination. Differentiation of CD34⁺ hematopoietic progenitors in vitro shows that cells with GATA1 antisense transcription have enhanced GATA2 transcription and a mast cell phenotype, whereas cells with GATA2 antisense transcription have increased GATA1 transcripts and an erythroblast phenotype. Detailed analyses of the AHR and RORC genes demonstrate the ability of competing promoters to act as binary switches and the association of antisense transcription with an immature/progenitor cell phenotype. These data indicate that alternative cell fates generated by promoter competition in lineage-determining transcription factors contribute to the programming of cell differentiation.

Keywords: AHR; CP: Molecular biology; CP: Stem cell research; GATA1; GATA2; RORC; antisense transcription; cell differentiation; divergent/convergent transcription; lineage determining; transcription factors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / genetics
GATA1 Transcription Factor* / metabolism
GATA2 Transcription Factor / genetics
GATA2 Transcription Factor / metabolism
Humans
Mice
Promoter Regions, Genetic / genetics
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Transcription Factors
GATA1 Transcription Factor
GATA2 Transcription Factor

Abstract

Publication types

MeSH terms

Substances

Grants and funding