LncRNA Ctcflos orchestrates transcription and alternative splicing in thermogenic adipogenesis

Abstract

The recruitment of thermogenic brite adipocytes within white adipose tissue attenuates obesity and metabolic comorbidities, arousing interest in understanding the underlying regulatory mechanisms. The molecular network of brite adipogenesis, however, remains largely unresolved. In this light, long noncoding RNAs (lncRNAs) emerged as a versatile class of modulators that control many steps within the differentiation machinery. Leveraging the naturally varying propensities of different inbred mouse strains for white adipose tissue browning, we identify the nuclear lncRNA Ctcflos as a pivotal orchestrator of thermogenic gene expression during brite adipocyte differentiation. Mechanistically, Ctcflos acts as a pleiotropic regulator, being essential for the transcriptional recruitment of the early core thermogenic regulatory program and the modulation of alternative splicing to drive brite adipogenesis. This is showcased by Ctcflos-regulated gene transcription and splicing of the key browning factor Prdm16 toward the isoform that is specific for the thermogenic gene program. Conclusively, our findings emphasize the mechanistic versatility of lncRNAs acting at several independent levels of gene expression for effective regulation of key differentiation factors to direct cell fate and function.

Long non-coding RNAs are involved in alternative splicing and promote cancer progression

“…The lncRNA GOMAFU can change the AS events of schizophrenia-related genes DISC1 and ERBB4 , and GOMAFU can interact with splicing factors QKI and SRSF1, which may be the mechanism of GOMAFU participating in the AS process [ 84 ]. The lncRNA Ctcflos is an important regulator of PRDM16, a key Brite fat-forming factor, which can regulate the splicing variant’s abundance of PRDM16, and then microregulate its function to regulate the production of Brite fat, which has research value in the treatment of obesity diseases and related comorbidities [ 85 ]. Therefore, the mechanism of lncRNA-associated AS in other diseases is worth in-depth study.…”

Comprehensive Transcriptional Profiling and Mouse Phenotyping Reveals Dispensable Role for Adipose Tissue Selective Long Noncoding RNA Gm15551

“…Compared to coding genes, lncRNAs are on average lower expressed, but show more tissue and developmental stage-specific expression profiles, advocating for a role as fine-tuning regulators of cellular function [ 16 ]. Selected lncRNAs have been shown to interfere with adipose tissue function and differentiation such as lncBATE10 , which acts as a decoy for CELF1, which would otherwise bind to and repress Pgc1a mRNA [ 17 ], H19 , which functions as a BAT-specific gatekeeper of paternally expressed genes [ 18 ], and Ctcflos, which regulates the expression and splicing of Prdm16 [ 19 ]. However, their overall contribution to these processes remains elusive.…”

Comprehensive transcriptional profiling and mouse phenotyping reveals dispensable role for adipose tissue selective long noncoding RNA Gm15551

“…In order to identify lncRNAs implicated in the regulation of iBAT function we set out to perform total RNA-seq on C57BL/6N mice put on a high fat diet regime from 8 weeks of age onwards for 12 weeks and additionally housed at 4 . Noteworthy, our analysis identified known brown adipose marker genes such as Ucp1 and Adcy3 as well as the lncRNA genes LncBate10 and Ctcflos, which have previously been shown to play a role in regulation of brown/beige adipose tissue function (Bai et al, 2017;Bast-Habersbrunner et al, 2021), proving the applicability of our strategy towards the identification of novel candidate adipose regulating lncRNAs. In order to rule out that any of the identified lncRNA genes were differentially regulated because of an increased immune cell infiltration of the iBAT caused by the cold or HFD treatment (Alcalá et al, 2017), we checked the expression profiles of several immune cell marker genes (Henriques et al, 2020), of which none were differentially regulated (Fig S1H).…”

“…Compared to coding genes, lncRNAs are on average lower expressed but show more tissue and developmental stage specific expression profiles, advocating for a role as fine tuning regulators of cellular function (Derrien et al, 2012). Selected lncRNAs have been shown to interfere with adipose tissue function and differentiation such as lncBATE10 which acts as a decoy for Celf1 which would otherwise bind to and repress Pgc1a mRNA (Bai et al, 2017), H19 which functions as a BAT-specific gatekeeper of paternally expressed genes (Schmidt et al, 2018) and Ctcflos which regulated expression and splicing of Prdm16 (Bast-Habersbrunner et al, 2021). However, their overall contribution to these processes remains elusive.…”