Alternative SET/TAFI Promoters Regulate Embryonic Stem Cell Differentiation

• Published in: Stem cell reports Vol. 9; no. 4; pp. 1291 - 1303
• Main Authors: Edupuganti, Raghu Ram, Harikumar, Arigela, Aaronson, Yair, Biran, Alva, Sailaja, Badi Sri, Nissim-Rafinia, Malka, Azad, Gajendra Kumar, Cohen, Malkiel A., Park, Jung Eun, Shivalila, Chikdu S., Markoulaki, Styliani, Sze, Siu Kwan, Jaenisch, Rudolf, Meshorer, Eran
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2017; Elsevier
• Subjects: Animals; Cell Differentiation - genetics; Cell Proliferation; Cell Survival - genetics; chromatin; Chromatin Assembly and Disassembly; differentiation; embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; epigenetics; Gene Expression Regulation, Developmental; Histone Acetyltransferases - genetics; histone chaperone; histone dynamics; Histones - metabolism; Mice; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Neoplasm Proteins - genetics; Nerve Tissue Proteins - genetics; Neural Plate - cytology; Octamer Transcription Factor-3 - metabolism; pluripotency; Promoter Regions, Genetic; Protein Isoforms; SET; TAF-I; TAFI; TATA-Binding Protein Associated Factors - genetics; Transcription Factor TFIID - genetics; differentiation; SET; embryonic stem cells; TAFI; histone dynamics; pluripotency; TAF-I; chromatin; histone chaperone; epigenetics
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2017.08.021

Embryonic stem cells (ESCs) are regulated by pluripotency-related transcription factors in concert with chromatin regulators. To identify additional stem cell regulators, we screened a library of endogenously labeled fluorescent fusion proteins in mouse ESCs for fluorescence loss during differentiation. We identified SET, which displayed a rapid isoform shift during early differentiation from the predominant isoform in ESCs, SETα, to the primary isoform in differentiated cells, SETβ, through alternative promoters. SETα is selectively bound and regulated by pluripotency factors. SET depletion causes proliferation slowdown and perturbed neuronal differentiation in vitro and developmental arrest in vivo, and photobleaching methods demonstrate SET's role in maintaining a dynamic chromatin state in ESCs. This work identifies an important regulator of pluripotency and early differentiation, which is controlled by alternative promoter usage. [Display omitted] •We identify SETα to be rapidly downregulated during ESC differentiation•SETα is regulated by pluripotency factors and replaced by SETβ during differentiation•SETα/SETβ switch is crucial for ESC differentiation•SETα regulates chromatin plasticity in ESCs In this article, Meshorer and colleagues screen the endogenously tagged fluorescent library they generated (see the accompanying paper by Harikumar et al.) and identify a linker histone chaperone, SET/TAF-I, to be involved in regulating mouse ESC pluripotency and early differentiation decisions. They show that SET has two isoforms regulated by alternative promoters and pluripotency factors, which are switched during early differentiation. SETα/SETβ replacement is important for ESC differentiation.