HoxBlinc RNA Recruits Set1/MLL Complexes to Activate Hox Gene Expression Patterns and Mesoderm Lineage Development

Changwang Deng, Ying Li, Lei Zhou, Joonseok Cho, Bhavita Patel, Naohiro Terada, Yangqiu Li, Jörg Bungert, Yi Qiu, Suming Huang

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Trithorax proteins and long-intergenic noncoding RNAs are critical regulators of embryonic stem cell pluripotency; however, how they cooperatively regulate germ layer mesoderm specification remains elusive. We report here that HoxBlinc RNA first specifies Flk1+ mesoderm and then promotes hematopoietic differentiation through regulation of hoxb pathways. HoxBlinc binds to the hoxb genes, recruits Setd1a/MLL1 complexes, and mediates long-range chromatin interactions to activate transcription of the hoxb genes. Depletion of HoxBlinc by shRNA-mediated knockdown or CRISPR-Cas9-mediated genetic deletion inhibits expression of hoxb genes and other factors regulating cardiac/hematopoietic differentiation. Reduced hoxb expression is accompanied by decreased recruitment of Set1/MLL1 and H3K4me3 modification, as well as by reduced chromatin loop formation. Re-expression of hoxb2-b4 genes in HoxBlinc-depleted embryoid bodies rescues Flk1+ precursors that undergo hematopoietic differentiation. Thus, HoxBlinc plays an important role in controlling hoxb transcription networks that mediate specification of mesoderm-derived Flk1+ precursors and differentiation of Flk1+ cells into hematopoietic lineages. Hoxb genes play a critical role in mesoderm and hematopoietic development. Deng et al. find that HoxBlinc RNA specifies hemangiogenic/cardiogenic mesoderm and promotes hematopoietic development by upregulating hoxb gene expression. HoxBlinc acts as a regulator of chromatin loop structure by guiding Setd1a/MLL1 to hoxb genes to control lineage-specific transcription.

Original languageEnglish (US)
Pages (from-to)103-114
Number of pages12
JournalCell Reports
Volume14
Issue number1
DOIs
StatePublished - Jan 5 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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