IRF2 is a master regulator of human keratinocyte stem cell fate

被引：18

作者：

Mercado, Nicolas ^{[1
]}

Schutzius, Gabi ^{[1
]}

Kolter, Christian ^{[1
]}

Estoppey, David ^{[1
]}

Bergling, Sebastian ^{[1
]}

Roma, Guglielmo ^{[1
]}

Keller, Caroline Gubser ^{[1
]}

Nigsch, Florian ^{[1
]}

Salathe, Adrian ^{[1
]}

Terranova, Remi ^{[2
]}

Reece-Hoyes, John ^{[3
]}

Alford, John ^{[3
]}

Russ, Carsten ^{[3
]}

Knehr, Judith ^{[1
]}

Hoepfner, Dominic ^{[1
]}

Aebi, Alexandra ^{[1
]}

Ruffner, Heinz ^{[1
]}

Beck, Tanner C. ^{[4
]}

Jagannathan, Sajjeev ^{[4
]}

Olson, Calla M. ^{[4
]}

Sheppard, Hadley E. ^{[5
]}

Elsarrag, Selma Z. ^{[5
]}

Bouwmeester, Tewis ^{[1
]}

Frederiksen, Mathias ^{[4
]}

Lohmann, Felix ^{[6
]}

Lin, Charles Y. ^{[4
,5
]}

Kirkland, Susan ^{[1
]}

机构：

[1] Novartis Pharma AG, Novartis Inst Biomed Res, Chem Biol & Therapeut, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland

[2] NIBR, Preclin Safety Translat Med, CH-4057 Basel, Switzerland

[3] Novartis Inst Biomed Res, Chem Biol & Therapeut, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[4] Baylor Coll Med, Dept Biochem & Mol Biol, Therapeut Innovat Ctr, 1 Baylor Plaza, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Mol & Human Genet, 1 Baylor Plaza, Houston, TX 77030 USA

[6] NIBR, Autoimmun Transplantat & Inflammat, CH-4056 Basel, Switzerland

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

TRANSCRIPTIONAL REGULATION; SERIAL CULTIVATION; SUPER-ENHANCERS; SENESCENCE; SKIN; PROLIFERATION; DIFFERENTIATION; INFLAMMATION; CHROMATIN; REGENERATION;

D O I：

10.1038/s41467-019-12559-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Resident adult epithelial stem cells maintain tissue homeostasis by balancing self-renewal and differentiation. The stem cell potential of human epidermal keratinocytes is retained in vitro but lost over time suggesting extrinsic and intrinsic regulation. Transcription factorcontrolled regulatory circuitries govern cell identity, are sufficient to induce pluripotency and transdifferentiate cells. We investigate whether transcriptional circuitry also governs phenotypic changes within a given cell type by comparing human primary keratinocytes with intrinsically high versus low stem cell potential. Using integrated chromatin and transcriptional profiling, we implicate IRF2 as antagonistic to stemness and show that it binds and regulates active cis-regulatory elements at interferon response and antigen presentation genes. CRISPR-KD of IRF2 in keratinocytes with low stem cell potential increases self-renewal, migration and epidermis formation. These data demonstrate that transcription factor regulatory circuitries, in addition to maintaining cell identity, control plasticity within cell types and offer potential for therapeutic modulation of cell function.

引用

页数：19

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