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Diverse Functions of Multiple Bdnf Transcripts Driven by Distinct Bdnf Promoters.

ABSTRACT: The gene encoding brain-derived neurotrophic factor (Bdnf) consists of nine non-coding exons driven by unique promoters, leading to the expression of nine Bdnf transcripts that play different roles in various brain regions and physiological stages. In this manuscript, we present a comprehensive overview of the molecular regulation and structural characteristics of the multiple Bdnf promoters, along with a summary of the current knowledge on the cellular and physiological functions of the distinct Bdnf transcripts produced by these promoters. Specifically, we summarized the role of Bdnf transcripts in psychiatric disorders, including schizophrenia and anxiety, as well as the cognitive functions associated with specific Bdnf promoters. Moreover, we examine the involvement of different Bdnf promoters in various aspects of metabolism. Finally, we propose future research directions that will enhance our understanding of the complex functions of Bdnf and its diverse promoters.

SUBMITTER: You H

PROVIDER: S-EPMC10135494 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Diverse Functions of Multiple Bdnf Transcripts Driven by Distinct Bdnf Promoters.

You He H Lu Bai B

Biomolecules 20230406 4

The gene encoding brain-derived neurotrophic factor (Bdnf) consists of nine non-coding exons driven by unique promoters, leading to the expression of nine Bdnf transcripts that play different roles in various brain regions and physiological stages. In this manuscript, we present a comprehensive overview of the molecular regulation and structural characteristics of the multiple Bdnf promoters, along with a summary of the current knowledge on the cellular and physiological fun ...[more]

PMID: 37189402

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Project description:MRG15/MORF4L1 is a highly conserved protein in eukaryotes that contains a chromodomain (CHD) recognizing methylation of lysine 36 on histone H3 (H3K36me3) in chromatin. Intriguingly, it has been reported in the literature to interact with several different factors involved in chromatin modifications, gene regulation, alternative mRNA splicing, and DNA repair by homologous recombination. To get a complete and reliable picture of associations in physiological conditions, we used genome editing and tandem affinity purification to analyze the stable native interactome of human MRG15, its paralog MRGX/MORF4L2 that lacks the CHD, and MRGBP (MRG-binding protein) in isogenic K562 cells. We found stable interchangeable association of MRG15 and MRGX with the NuA4/TIP60 histone acetyltransferase/chromatin remodeler, Sin3B histone deacetylase/demethylase, ASH1L histone methyltransferase, and PALB2-BRCA2 DNA repair protein complexes. These associations were further confirmed and analyzed by CRISPR tagging of endogenous proteins and comparison of expressed isoforms. Importantly, based on structural information, point mutations could be introduced that specifically disrupt MRG15 association with some complexes but not others. Most interestingly, we also identified a new abundant native complex formed by MRG15/X-MRGBP-BRD8-EP400NL (EP400 N-terminal like) that is functionally similar to the yeast TINTIN (Trimer Independent of NuA4 for Transcription Interactions with Nucleosomes) complex. Our results show that EP400NL, being homologous to the N-terminal region of NuA4/TIP60 subunit EP400, creates TINTIN by competing for BRD8 association. Functional genomics indicate that human TINTIN plays a role in transcription of specific genes. This is most likely linked to the H4ac-binding bromodomain of BRD8 along the H3K36me3-binding CHD of MRG15 on the coding region of transcribed genes. Taken together, our data provide a complete detailed picture of human MRG proteins-associated protein complexes, which are essential to understand and correlate their diverse biological functions in chromatin-based nuclear processes.

Dataset Information

Diverse Functions of Multiple Bdnf Transcripts Driven by Distinct Bdnf Promoters.

Publications

Diverse Functions of Multiple <i>Bdnf</i> Transcripts Driven by Distinct <i>Bdnf</i> Promoters.

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