Pluripotency factors functionally premark cell-type-restricted enhancers in ES cells

Hong Sook Kim (), Yuliang Tan, Wubin Ma, Daria Merkurjev, Eugin Destici, Qi Ma, Tom Suter, Kenneth Ohgi, Meyer Friedman, Dorota Skowronska-Krawczyk and Michael G. Rosenfeld ()
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Hong Sook Kim: University of California San Diego
Yuliang Tan: University of California San Diego
Wubin Ma: University of California San Diego
Daria Merkurjev: University of California San Diego
Eugin Destici: University of California San Diego
Qi Ma: University of California San Diego
Tom Suter: University of California San Diego
Kenneth Ohgi: University of California San Diego
Meyer Friedman: University of California San Diego
Dorota Skowronska-Krawczyk: University of California San Diego
Michael G. Rosenfeld: University of California San Diego

Nature, 2018, vol. 556, issue 7702, 510-514

Abstract: Abstract Enhancers for embryonic stem (ES) cell-expressed genes and lineage-determining factors are characterized by conventional marks of enhancer activation in ES cells1–3, but it remains unclear whether enhancers destined to regulate cell-type-restricted transcription units might also have distinct signatures in ES cells. Here we show that cell-type-restricted enhancers are ‘premarked’ and activated as transcription units by the binding of one or two ES cell transcription factors, although they do not exhibit traditional enhancer epigenetic marks in ES cells, thus uncovering the initial temporal origins of cell-type-restricted enhancers. This premarking is required for future cell-type-restricted enhancer activity in the differentiated cells, with the strength of the ES cell signature being functionally important for the subsequent robustness of cell-type-restricted enhancer activation. We have experimentally validated this model in macrophage-restricted enhancers and neural precursor cell (NPC)-restricted enhancers using ES cell-derived macrophages or NPCs, edited to contain specific ES cell transcription factor motif deletions. DNA hydroxyl-methylation of enhancers in ES cells, determined by ES cell transcription factors, may serve as a potential molecular memory for subsequent enhancer activation in mature macrophages. These findings suggest that the massive repertoire of cell-type-restricted enhancers are essentially hierarchically and obligatorily premarked by binding of a defining ES cell transcription factor in ES cells, dictating the robustness of enhancer activation in mature cells.

Date: 2018
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DOI: 10.1038/s41586-018-0048-8

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