Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition

Mattia Zaghi, Federica Banfi, Luca Massimino, Monica Volpin, Edoardo Bellini, Simone Brusco, Ivan Merelli, Cristiana Barone, Michela Bruni, Linda Bossini, Luigi Antonio Lamparelli, Laura Pintado, Deborah D’Aliberti, Silvia Spinelli, Luca Mologni, Gaia Colasante, Federica Ungaro, Jean-Michel Cioni, Emanuele Azzoni, Rocco Piazza, Eugenio Montini, Vania Broccoli and Alessandro Sessa ()
Additional contact information
Mattia Zaghi: IRCCS San Raffaele Scientific Institute
Federica Banfi: IRCCS San Raffaele Scientific Institute
Luca Massimino: IRCCS San Raffaele Scientific Institute
Monica Volpin: San Raffaele Scientific Institute
Edoardo Bellini: IRCCS San Raffaele Scientific Institute
Simone Brusco: IRCCS San Raffaele Scientific Institute
Ivan Merelli: CNR Institute of Biomedical Technologies
Cristiana Barone: University of Milano-Bicocca
Michela Bruni: IRCCS San Raffaele Scientific Institute
Linda Bossini: IRCCS San Raffaele Scientific Institute
Luigi Antonio Lamparelli: IRCCS San Raffaele Scientific Institute
Laura Pintado: IRCCS San Raffaele Scientific Institute
Deborah D’Aliberti: University of Milano-Bicocca
Silvia Spinelli: University of Milano-Bicocca
Luca Mologni: University of Milano-Bicocca
Gaia Colasante: IRCCS San Raffaele Scientific Institute
Federica Ungaro: IRCCS San Raffaele Scientific Institute
Jean-Michel Cioni: IRCCS San Raffaele Scientific Institute
Emanuele Azzoni: University of Milano-Bicocca
Rocco Piazza: University of Milano-Bicocca
Eugenio Montini: San Raffaele Scientific Institute
Vania Broccoli: IRCCS San Raffaele Scientific Institute
Alessandro Sessa: IRCCS San Raffaele Scientific Institute

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Within the chromatin, distal elements interact with promoters to regulate specific transcriptional programs. Histone acetylation, interfering with the net charges of the nucleosomes, is a key player in this regulation. Here, we report that the oncoprotein SET is a critical determinant for the levels of histone acetylation within enhancers. We disclose that a condition in which SET is accumulated, the severe Schinzel-Giedion Syndrome (SGS), is characterized by a failure in the usage of the distal regulatory regions typically employed during fate commitment. This is accompanied by the usage of alternative enhancers leading to a massive rewiring of the distal control of the gene transcription. This represents a (mal)adaptive mechanism that, on one side, allows to achieve a certain degree of differentiation, while on the other affects the fine and corrected maturation of the cells. Thus, we propose the differential in cis-regulation as a contributing factor to the pathological basis of SGS and possibly other the SET-related disorders in humans.

Date: 2023
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DOI: 10.1038/s41467-023-39043-x

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