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

Mattia, Z.; Banfi, F.; Massimino, L.; Volpin, M.; Bellini, E.; Brusco, S.; Merelli, I.; Barone, C.; Bruni, M.; Bossini, L.; Lamparelli, L. A.; Pintado, L.; Spinelli, S.; Mologni, L.; Colasante, G.; Ungaro, F.; Cioni, J.-M.; Azzoni, E.; Piazza, R.; Montini, E.; Broccoli, V.; Sessa, A.

2022-09-13 developmental biology
10.1101/2022.09.12.507599 bioRxiv
Show 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 onco-protein SET is a critical determinant for the levels of histone acetylation within enhancers. We disclose that conditions in which SET is accumulated, including the severe Schinzel-Giedion Syndrome (SGS), are 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 the SET-related disorders in humans, including SGS, neurodevelopmental disorders, myeloproliferative diseases, and cancer.

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