SOX17 integrates HOXA and arterial programs in hemogenic endothelium to drive definitive lympho-myeloid hematopoiesis | Zendy

Ho Sun Jung | Zendy; Gene I. Uenishi | Zendy; Mi Ae Park | Zendy; Peng Liu | Zendy; Kran Suknuntha | Zendy; Matthew Raymond | Zendy; Yoon Jung Choi | Zendy; James A. Thomson | Zendy; Irene M. Ong | Zendy; Igor I. Slukvin | Zendy

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SOX17 integrates HOXA and arterial programs in hemogenic endothelium to drive definitive lympho-myeloid hematopoiesis

Author(s) -

Ho Sun Jung,

Gene I. Uenishi,

Mi Ae Park,

Peng Liu,

Kran Suknuntha,

Matthew Raymond,

Yoon Jung Choi,

James A. Thomson,

Irene M. Ong,

Igor I. Slukvin

Publication year - 2021

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2021.108758

Subject(s) - haematopoiesis , regulator , induced pluripotent stem cell , notch signaling pathway , stem cell , biology , cxcr4 , microbiology and biotechnology , myeloid , runx1 , phenotype , cancer research , embryonic stem cell , immunology , genetics , signal transduction , gene , chemokine , immune system

SUMMARY SOX17 has been implicated in arterial specification and the maintenance of hematopoietic stem cells (HSCs) in the murine embryo. However, knowledge about molecular pathways and stage-specific effects of SOX17 in humans remains limited. Here, using SOX17-knockout and SOX17-inducible human pluripotent stem cells (hPSCs), paired with molecular profiling studies, we reveal that SOX17 is a master regulator of HOXA and arterial programs in hemogenic endothelium (HE) and is required for the specification of HE with robust lympho-myeloid potential and DLL4 + CXCR4 + phenotype resembling arterial HE at the sites of HSC emergence. Along with the activation of NOTCH signaling, SOX17 directly activates CDX2 expression, leading to the upregulation of the HOXA cluster genes. Since deficiencies in HOXA and NOTCH signaling contribute to the impaired in vivo engraftment of hPSC-derived hematopoietic cells, the identification of SOX17 as a key regulator linking arterial and HOXA programs in HE may help to program HSC fate from hPSCs.

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