Pontin Functions as A Transcriptional Co-activator for Retinoic Acid-induced HOX Gene Expression

JOURNAL OF MOLECULAR BIOLOGY

卷:433

Article

Tang, Dan^1,2  Zhang, Zhao¹  Zboril, Emily¹  Wetzel, Michael D.¹  Xu, Xinping³  Zhang, Wei³  Chen, Lizhen^1,4  Liu, Zhijie¹ 

[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA

[2] Nanchang Univ, Dept Gen Practice, Affiliated Hosp 1, Nanchang 330006, Jiangxi, Peoples R China

[3] Nanchang Univ, Jiangxi Inst Resp Dis, Dept Resp & Crit Care Med, Affiliated Hosp 1, Nanchang 330006, Jiangxi, Peoples R China

[4] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, Dept Cell Syst & Anat, San Antonio, TX 78229 USA

关键词: pontin;    retinoic acid;    HOX gene;    transcriptional co-activator;    embryonic development;   

DOI  :  10.1016/j.jmb.2021.166928

来源: Elsevier

【 摘 要 】

Pontin is a AAA+ ATPase protein that has functions in various biological contexts including gene transcription regulation, chromatin remodeling, DNA damage sensing and repair, as well as assembly of protein and ribonucleoprotein complexes. Pontin is known to regulate the transcription of several important signaling pathways, including Wnt signaling. However, its role in early embryonic signaling regulation remains unclear. Retinoic acid (RA) signaling plays a central role in vertebrate development. Using an in vivo biotin tagging technology, we mapped the genome-wide binding pattern of Pontin before and after RA-induced differentiation in the pluripotent embryo carcinoma cell line NTERA-2. Biotin ChIP-seq revealed significant changes in genome-wide Pontin binding sites upon RA stimulation. We also identified a substantial amount of overlapping binding peaks between Pontin and RAR alpha, especially on all of the HOX gene loci (A-D clusters). Pontin knockdown experiments showed that its chromatin binding at the HOX gene clusters is required for RA-induced HOX gene expression. Furthermore, we performed Global Run-On sequencing (GRO-seq) to map de novo transcripts genome-wide and found that Pontin knockdown significantly diminished nascent HOX gene transcripts, indicating that Pontin regulates HOX gene expression at the transcriptional level. Finally, proteomic analysis demonstrated that Pontin associates with chromatin organization/remodeling complexes and various other functional complexes. Altogether, we have demonstrated that Pontin is a critical transcriptional co-activator for RA-induced HOX gene activation. (C) 2021 Elsevier Ltd. All rights reserved.

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