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1.
Cell ; 186(20): 4365-4385.e27, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37774677

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology.


Assuntos
Doença de Alzheimer , Encéfalo , Idoso , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Cognição , Disfunção Cognitiva/metabolismo , Neurônios/metabolismo
2.
Elife ; 122023 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-37665675

RESUMO

Alternative polyadenylation (APA) generates mRNA isoforms and diversifies gene expression. Here we report the discovery that the mTORC1 signaling pathway balances the expression of two Trim9/TRIM9 isoforms through APA regulation in human and mouse. We showed that CFIm components, CPSF6 and NUDT21, promote the short Trim9/TRIM9 isoform (Trim9-S/TRIM9-S) expression. In addition, we identified an evolutionarily conserved twin UGUA motif, UGUAYUGUA, in TRIM9-S polyadenylation site (PAS) that is critical for its regulation by CPSF6. We found additional CPSF6-regulated PASs with similar twin UGUA motifs in human and experimentally validated the twin UGUA motif functionality in BMPR1B, MOB4, and BRD4-L. Importantly, we showed that inserting a twin UGUA motif into a heterologous PAS was sufficient to confer regulation by CPSF6 and mTORC1. Our study reveals an evolutionarily conserved mechanism to regulate gene isoform expression by mTORC1 and implicates possible gene isoform imbalance in cancer and neurological disorders with mTORC1 pathway dysregulation.


Assuntos
Proteínas Nucleares , Fatores de Transcrição , Humanos , Animais , Camundongos , Transdução de Sinais , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Isoformas de Proteínas/genética , Proteínas de Ciclo Celular , Proteínas do Tecido Nervoso , Ubiquitina-Proteína Ligases
3.
Cell Rep ; 37(2): 109815, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34644577

RESUMO

DNA damage reshapes the cellular transcriptome by modulating RNA transcription and processing. In cancer cells, these changes can alter the expression of genes in the immune surveillance and cell death pathways. Here, we investigate how DNA damage impacts alternative polyadenylation (APA) using the PAPERCLIP technique. We find that APA shifts are a coordinated response for hundreds of genes to DNA damage, and we identify PCF11 as an important contributor of DNA damage-induced APA shifts. One of these APA shifts results in upregulation of the full-length MSL1 mRNA isoform, which protects cells from DNA damage-induced apoptosis and promotes cell survival from DNA-damaging agents. Importantly, blocking MSL1 upregulation enhances cytotoxicity of chemotherapeutic agents even in the absence of p53 and overcomes chemoresistance. Our study demonstrates that characterizing adaptive APA shifts to DNA damage has therapeutic implications and reveals a link between PCF11, the MSL complex, and DNA damage-induced apoptosis.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Dano ao DNA , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Histona Acetiltransferases/metabolismo , Neoplasias/tratamento farmacológico , Poliadenilação , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HeLa , Histona Acetiltransferases/genética , Humanos , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Transdução de Sinais , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo
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