RESUMO
Heat stress (HS) induces a cellular response leading to profound changes in gene expression. Here, we show that human YTHDC1, a reader of N6-methyladenosine (m6A) RNA modification, mostly associates to the chromatin fraction and that HS induces a redistribution of YTHDC1 across the genome, including to heat-induced heat shock protein (HSP) genes. YTHDC1 binding to m6A-modified HSP transcripts co-transcriptionally promotes expression of HSPs. In parallel, hundreds of the genes enriched in YTHDC1 during HS have their transcripts undergoing YTHDC1- and m6A-dependent intron retention. Later, YTHDC1 concentrates within nuclear stress bodies (nSBs) where it binds to m6A-modified SATIII non-coding RNAs, produced in an HSF1-dependent manner upon HS. These findings reveal that YTHDC1 plays a central role in a chromatin-associated m6A-based reprogramming of gene expression during HS. Furthermore, they support the model where the subsequent and temporary sequestration of YTHDC1 within nSBs calibrates the timing of this YTHDC1-dependent gene expression reprogramming.
Assuntos
Cromatina , Resposta ao Choque Térmico , Humanos , Resposta ao Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Expressão Gênica , Fatores de Processamento de RNA/metabolismo , Proteínas do Tecido Nervoso/metabolismoRESUMO
Oncogenesis involves continuous genetic alterations that lead to compromised cellular integrity and immortal cell fate. The cells remain under excessive stress due to endo- and exogenous influences. Human Satellite III long noncoding RNA (SatIII lncRNA) is a key regulator of the global cellular stress response, although its function is poorly explained in cancers. The principal regulator of cancer meshwork is tumor protein p53, which if altered may result in chemoresistance. The heat shock factor 1 (HSF1) being a common molecule between the oncogenic control and global cellular stress acts as an oncogene as well as transcribes SatIII upon heat shock. This prompted us to determine the structure of SatIII RNA and establish the association between SatIII-HSF1-p53. We determined the most stable structure of SatIII RNA with the least energy of - 115.7 kcal/mol. Also, we observed a possible interaction of p53 with SatIII and HSF1 using support vector machine (SVM) algorithm for predicting RNA-protein interaction (RPI). Further, we employ the STRING database to understand if p53 is an interacting component of the nuclear stress bodies (nSBs). A precise inference was drawn from molecular docking which confirmed the interaction of SatIII-HSF1-p53, where a mutated p53 resulted in an altered DNA-binding property with the SatIII molecule. This study being first of its kind infers p53 to be a possible integral component of the nSBs, which may regulate cellular stress response during cancer progression in the presence of HSF1 and SatIII. An extended research on the regulations of SatIII and p53 may open new avenues in the field of apoptosis in cancer and the early approach of molecular targeting.
Assuntos
Carcinogênese/patologia , Núcleo Celular/genética , Fatores de Transcrição de Choque Térmico/metabolismo , RNA Longo não Codificante/metabolismo , RNA Satélite/metabolismo , Estresse Fisiológico , Proteína Supressora de Tumor p53/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Células HeLa , Fatores de Transcrição de Choque Térmico/química , Fatores de Transcrição de Choque Térmico/genética , Resposta ao Choque Térmico , Humanos , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Conformação Proteica , RNA Longo não Codificante/química , RNA Longo não Codificante/genética , RNA Satélite/química , RNA Satélite/genética , Transcrição Gênica , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genéticaRESUMO
Aspergillus niger is usually regarded as a beneficial species widely used in biotechnological industry. Obtaining the genome sequence of the widely used aconidial A. niger SH2 strain is of great importance to understand its unusual production capability. In this study we assembled a high-quality genome sequence of A. niger SH2 with approximately 11,517 ORFs. Relatively high proportion of genes enriched for protein expression related FunCat items verify its efficient capacity in protein production. Furthermore, genome-wide comparative analysis between A. niger SH2 and CBS513.88 reveals insights into unique properties of A. niger SH2. A. niger SH2 lacks the gene related with the initiation of asexual sporulation (PrpA), leading to its distinct aconidial phenotype. Frame shift mutations and non-synonymous SNPs in genes of cell wall integrity signaling, ß-1,3-glucan synthesis and chitin synthesis influence its cell wall development which is important for its hyphal fragmentation during industrial high-efficiency protein production.