Defining a cohort of anemia-activated cis elements reveals a mechanism promoting erythroid precursor function

Yichao Zhou, Venkatasai Rahul Dogiparthi, Suhita Ray, Meg A. Schaefer, Hannah L. Harris, M. Jordan Rowley, Kyle J. Hewitt

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Acute anemia elicits broad transcriptional changes in erythroid progenitors and precursors. We previously discovered a cis-regulatory transcriptional enhancer at the sterile alpha motif domain-14 enhancer locus (S14E), defined by a CANNTG-spacer-AGATAA composite motif and occupied by GATA1 and TAL1 transcription factors, is required for survival in severe anemia. However, S14E is only 1 of dozens of anemia-activated genes containing similar motifs. In a mouse model of acute anemia, we identified populations of expanding erythroid precursors, which increased expression of genes that contain S14E-like cis elements. We reveal that several S14E-like cis elements provide important transcriptional control of newly identified anemia-inducing genes, including the Ssx-2 interacting protein (Ssx2ip). Ssx2ip expression was determined to play an important role in erythroid progenitor/precursor cell activities, cell cycle regulation, and cell proliferation. Over a weeklong course of acute anemia recovery, we observed that erythroid gene activation mediated by S14E-like cis elements occurs during a phase coincident with low hematocrit and high progenitor activities, with distinct transcriptional programs activated at earlier and later time points. Our results define a genome-wide mechanism in which S14E-like enhancers control transcriptional responses during erythroid regeneration. These findings provide a framework to understand anemia-specific transcriptional mechanisms, ineffective erythropoiesis, anemia recovery, and phenotypic variability within human populations.

Original languageEnglish (US)
Pages (from-to)6325-6338
Number of pages14
JournalBlood Advances
Volume7
Issue number20
DOIs
StatePublished - Oct 24 2023

ASJC Scopus subject areas

  • Hematology

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