RNA-Binding Proteins in the Regulation of Adipogenesis and Adipose Function

Zhang, Pengpeng; Wu, Wenyan; Ma, Chaofeng; Du, Chunyu; Huang, Yueru; Xu, Haixia; Li, Cencen; Cheng, Xiangdong; Hao, Ruijie; Xu, Yongjie

doi:10.3390/cells11152357

Cited by 19 publications

(12 citation statements)

References 134 publications

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“…Additionally, we note associated increased expression of HuR/ Elavl1 and Igf2bp2 , and decreased expression Nova2 , Pspc1 , and many serine-arginine rich splicing factors in BAT from mice housed at SC vs TN. This suggests that expression of RNA-binding proteins known to mediate alternative splicing in adipose tissues is also altered during chronic cold stress (Chao et al, 2021; Vernia et al, 2016; Zhang et al, 2022). Our results indicate the need for further studies to better characterize the mechanism(s) driving alternative splicing events in BAT, as well as the biological function of alternative splice variants that are expressed in BAT, in response to chronic cold stress.…”

Section: Discussionmentioning

confidence: 99%

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress

Taylor,

Steinthal,

Dias

et al. 2023

Preprint

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Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Motivated to understand how BAT function is regulated epigenetically, we reanalyzed publicly available RNA-seq data and uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28.8°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C). BAT and reference tissue liver were subsequently dissected from each mouse. Reduced representation bisulfite sequencing (RRBS) reveals decreased methylation of promoters and intragenic regions in BAT genomic DNA in response to varying degrees of chronic cold exposure. Integration of our RRBS and the RNA-Seq dataset suggests a role for epigenetic modification of DNA in gene regulation in response to cold. To analyze histone modifications in BAT, we develop a robust method for the isolation of histones and report the first quantitation of histone H3.2 and H4 proteoforms. We initially observe that BAT and liver exhibit different histone proteoforms. Next, we report housing temperature-dependent changes in histone proteoforms in BAT. We observe differences in bivalent proteoforms such as H3{K9me2,K23ac,K36me1}, H3{K9me3,K23ac,K36me1} and H4<K8acK16acK20me3>. Taken together, our results provide novel findings supporting global epigenetic modification in murine BAT in response to varying degrees of chronic cold stimuli and establish a methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response.

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Section: Discussionmentioning

confidence: 99%

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress

Taylor,

Steinthal,

Dias

et al. 2023

Preprint

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“…We described 14 loops at its promoter ( Table 1 ), reflecting its high potential of interaction with other distally located genomic regions. Other genes related to obesity and/or adipogenesis were identified by our HiChIP analysis as regulators of ABD vs. GF gene transcription, such as METTL15 [ 56 ] and RBM4 [ 57 ]. Overall, our study supports the idea that long-range chromatin loops may affect the development or differentiation of ADSCs and could explain in part subcutaneous adipose tissue dysfunction in diseases such as T2D or PCOS.…”

Section: Discussionmentioning

confidence: 99%

An Atlas of Promoter Chromatin Modifications and HiChIP Regulatory Interactions in Human Subcutaneous Adipose-Derived Stem Cells

Halasz,

Divoux,

Sandor

et al. 2023

IJMS

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The genome of human adipose-derived stem cells (ADSCs) from abdominal and gluteofemoral adipose tissue depots are maintained in depot-specific stable epigenetic conformations that influence cell-autonomous gene expression patterns and drive unique depot-specific functions. The traditional approach to explore tissue-specific transcriptional regulation has been to correlate differential gene expression to the nearest-neighbor linear-distance regulatory region defined by associated chromatin features including open chromatin status, histone modifications, and DNA methylation. This has provided important information; nonetheless, the approach is limited because of the known organization of eukaryotic chromatin into a topologically constrained three-dimensional network. This network positions distal regulatory elements in spatial proximity with gene promoters which are not predictable based on linear genomic distance. In this work, we capture long-range chromatin interactions using HiChIP to identify remote genomic regions that influence the differential regulation of depot-specific genes in ADSCs isolated from different adipose depots. By integrating these data with RNA-seq results and histone modifications identified by ChIP-seq, we uncovered distal regulatory elements that influence depot-specific gene expression in ADSCs. Interestingly, a subset of the HiChIP-defined chromatin loops also provide previously unknown connections between waist-to-hip ratio GWAS variants with genes that are known to significantly influence ADSC differentiation and adipocyte function.

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“…SAM68 knockout leads to the production of a new transcript isoform Rps6kb1-002 in preadipocytes, promoted by SRSF1, thereby inhibiting adipogenesis and lipid accumulation. 175 Chao et al 176 and Zhang et al 177 integrated existing research results with specific ASEs and different functions of various AS regulatory factors as examples, highlighting the important role of AS mechanisms in adipogenesis and adipocyte biology. Among them, HuR, PSPC1, Sam68, RBM4, Ybx1, Ybx2, IGF2BP2, KSRP, and other RBPs play a key regulatory role.…”

Section: Alternative Splicing and Related Rbps In The Reproductive Sy...mentioning

confidence: 99%

Alternative splicing and related RNA binding proteins in human health and disease

Tao,

Zhang,

Wang

et al. 2024

Sig Transduct Target Ther

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Alternative splicing (AS) serves as a pivotal mechanism in transcriptional regulation, engendering transcript diversity, and modifications in protein structure and functionality. Across varying tissues, developmental stages, or under specific conditions, AS gives rise to distinct splice isoforms. This implies that these isoforms possess unique temporal and spatial roles, thereby associating AS with standard biological activities and diseases. Among these, AS-related RNA-binding proteins (RBPs) play an instrumental role in regulating alternative splicing events. Under physiological conditions, the diversity of proteins mediated by AS influences the structure, function, interaction, and localization of proteins, thereby participating in the differentiation and development of an array of tissues and organs. Under pathological conditions, alterations in AS are linked with various diseases, particularly cancer. These changes can lead to modifications in gene splicing patterns, culminating in changes or loss of protein functionality. For instance, in cancer, abnormalities in AS and RBPs may result in aberrant expression of cancer-associated genes, thereby promoting the onset and progression of tumors. AS and RBPs are also associated with numerous neurodegenerative diseases and autoimmune diseases. Consequently, the study of AS across different tissues holds significant value. This review provides a detailed account of the recent advancements in the study of alternative splicing and AS-related RNA-binding proteins in tissue development and diseases, which aids in deepening the understanding of gene expression complexity and offers new insights and methodologies for precision medicine.

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RNA-Binding Proteins in the Regulation of Adipogenesis and Adipose Function

Cited by 19 publications

References 134 publications

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress

An Atlas of Promoter Chromatin Modifications and HiChIP Regulatory Interactions in Human Subcutaneous Adipose-Derived Stem Cells

Alternative splicing and related RNA binding proteins in human health and disease

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