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M6A-modification of HSATIII lncRNAs regulates temperature-dependent splicing

ABSTRACT: Nuclear stress bodies (nSBs) are nuclear membraneless organelles formed around stress-inducible HSATIII architectural long noncoding RNAs (lncRNAs). nSBs repress splicing of hundreds of introns during thermal stress recovery, which are partly regulated by CLK1 kinase phosphorylation of temperature-dependent Ser/Arg-rich splicing factors (SRSFs). Here we report a distinct mechanism for this splicing repression through protein sequestration by nSBs. Comprehensive identification of RNA-binding proteins revealed HSATIII association with proteins related to N6-methyladenosine (m6A) RNA modification. 11% of the first adenosine in the repetitive HSATIII sequence were m6A-modified. nSBs sequester the m6A writer complex to methylate HSATIII, leading to subsequent sequestration of the nuclear m6A reader, YTHDC1. Sequestration of these factors from the nucleoplasm represses m6A modification of pre-mRNAs, leading to repression of m6A-dependent splicing during stress recovery phase. Thus, nSBs serve as a common platform for regulation of temperature-dependent splicing through dual mechanisms employing two distinct ribonucleoprotein modules with partially m6A-modified architectural lncRNAs.

SUBMITTER: Dr. Kensuke Ninomiya

PROVIDER: S-SCDT-EMBOJ-2021-107976 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Background:Fat percentage and distribution in pigs are associated with their productive efficiency and meat quality. Dietary branched-chain amino acids (BCAA) regulate fat metabolism in weanling piglets with unknown mechanism. It is reported that N6-methyl-adenosine (m6A) is involved in fat metabolism in mice. The current study was designed to investigate the relationship between dietary branched-chain amino acids and fat metabolism through N6-methyl-adenosine (m6A) in weanling piglets. Methods:A total of 18 healthy crossbred weaned piglets (Duroc × Landrace × Large White, 10.45?±?0.41?kg) were divided into 3 treatments and were fed the low BCAA dose diet (L-BCAA), the normal dose BCAA diet (N-BCAA), or the high dose BCAA (H-BCAA) diet for 3 weeks. Results:Our results show that compared with the N-BCAA group, the L-BCAA group had higher concentration of serum leptin (P?<?0.05), while the H-BCAA group had lower concentration of serum adiponectin (P?<?0.05). Fatty acid synthesis in pigs from the H-BCAA group was lower than those from the N-BCAA group with the down-regulation of lipogenic genes (ACACA, FASN, PPAR-r, SREBP-1c in ventral and dorsal fat, SREBP-1c in liver) and up-regulation of lipolysis genes (HSL, ATGL, CPT-1A, FABP4 in ventral fat, HSL in liver) (P?<?0.05). Similarly, fatty acid synthesis in pigs from the L-BCAA group was also lower than those from the N-BCAA group with the decrease of lipogenic genes (ACACA in ventral, ACACA and FASN in dorsal fat, ACACA, FASN, SREBP-1c in liver) and the increase of lipolysis genes (ATGL, CPT-1A CD36, FABP4 in ventral fat and HSL, ATGL, CPT-1A in dorsal fat, CPT-1A) (P?<?0.05). Feeding H-BCAA diet significantly reduced total m6A levels in ventral and dorsal fat and liver tissues (P?<?0.05). The decrease of total m6A is associated with down-regulation of METTL3, METTL14 and FTO in dorsal fat and METTL3 and FTO in liver (P?<?0.05). Decreased m6A modification of ACACA and FASN in ventral and dorsal adipose tissues was observed in pig fed with excessive BCAA. Conclusion:These results suggest that insufficient or excessive BCAA decreased the fat deposition by increasing lipolysis and deceasing lipogenesis in adipose and liver tissues. Dietary excessive BCAA might regulate the process of lipid metabolism partly through the m6A RNA methylation.

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M6A-modification of HSATIII lncRNAs regulates temperature-dependent splicing

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