RESUMO
Mammalian genomes harbor abundant transposable elements (TEs) and their remnants, with numerous epigenetic repression mechanisms enacted to silence TE transcription. However, TEs are upregulated during early development, neuronal lineage, and cancers, although the epigenetic factors contributing to the transcription of TEs have yet to be fully elucidated. Here, we demonstrate that the male-specific lethal (MSL)-complex-mediated histone H4 acetylation at lysine 16 (H4K16ac) is enriched at TEs in human embryonic stem cells (hESCs) and cancer cells. This in turn activates transcription of subsets of full-length long interspersed nuclear elements (LINE1s, L1s) and endogenous retrovirus (ERV) long terminal repeats (LTRs). Furthermore, we show that the H4K16ac-marked L1 and LTR subfamilies display enhancer-like functions and are enriched in genomic locations with chromatin features associated with active enhancers. Importantly, such regions often reside at boundaries of topologically associated domains and loop with genes. CRISPR-based epigenetic perturbation and genetic deletion of L1s reveal that H4K16ac-marked L1s and LTRs regulate the expression of genes in cis. Overall, TEs enriched with H4K16ac contribute to the cis-regulatory landscape at specific genomic locations by maintaining an active chromatin landscape at TEs.
Assuntos
Elementos de DNA Transponíveis , Retrovirus Endógenos , Animais , Humanos , Masculino , Elementos de DNA Transponíveis/genética , Cromatina/genética , Sequências Reguladoras de Ácido Nucleico/genética , Retrovirus Endógenos/genética , Genômica , Mamíferos/genéticaRESUMO
BACKGROUND: Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor. METHODS: We explore the therapeutic potential of BMI1 and MAPK/ERK inhibition in BMI1High;CHD7Low MB cells and in a preclinical xenograft model. RESULTS: We identify a synergistic vulnerability of BMI1High;CHD7Low MB cells to a combination treatment with BMI1 and MAPK/ERK inhibitors. Mechanistically, CHD7-dependent binding of BMI1 to MAPK-regulated genes underpins the CHD7-BMI1-MAPK regulatory axis responsible of the antitumour effect of the inhibitors in vitro and in a preclinical mouse model. Increased ERK1 and ERK2 phosphorylation activity is found in BMI1High;CHD7Low G4 MB patients, raising the possibility that they could be amenable to a similar therapy. CONCLUSIONS: The molecular dissection of the CHD7-BMI1-MAPK regulatory axis in BMI1High;CHD7Low MB identifies this signature as a proxy to predict MAPK functional activation, which can be effectively drugged in preclinical models, and paves the way for further exploration of combined BMI1 and MAPK targeting in G4 MB patients.
Assuntos
Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Inibidores de Proteínas Quinases , Animais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Cerebelares/genética , Humanos , Meduloblastoma/genética , Camundongos , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/genéticaRESUMO
The classical example of nonadditive contributions of the two parents to allopolyploids is nucleolar dominance, which entails silencing of one parental set of ribosomal RNA genes. This has been observed for many other loci. The prevailing explanation for this genome-wide expression disparity is that the two merged genomes differ in their transposable element (TE) complement and in their level of TE-mediated repression of gene expression. Alternatively, and not exclusively, gene expression dominance may arise from mismatches between trans effectors and their targets. Here, we explore quantitative models of regulatory mismatches leading to gene expression dominance. We also suggest that, when pairs of merged genomes are similar from one allopolyploidization event to another, gene-level and genome dominance patterns should also be similar.