Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 213/D, 41125 Modena, Italy.
Int J Mol Sci. 2022 Jul 27;23(15):8304. doi: 10.3390/ijms23158304.
Alternative splicing (AS) is a tightly regulated mechanism that generates the complex human proteome from a small number of genes. -regulatory RNA motifs in exons and introns control AS, recruiting positive and negative -acting splicing regulators. At a higher level, chromatin affects splicing events. Growing evidence indicates that the popular histone code hypothesis can be extended to RNA-level processes, such as AS. In addition to nucleosome positioning, which can generate transcriptional barriers to shape the final splicing outcome, histone post-translational modifications can contribute to the detailed regulation of single exon inclusion/exclusion. A histone-based system can identify alternatively spliced chromatin stretches, affecting RNAPII elongation locally or recruiting splicing components via adaptor complexes. In tumor cells, several mechanisms trigger misregulated AS events and produce cancer-associated transcripts. On a genome-wide level, aberrant AS can be the consequence of dysfunctional epigenetic splicing code, including altered enrichment in histone post-translational modifications. This review describes the main findings related to the effect of histone modifications and variants on splicing outcome and how a dysfunctional epigenetic splicing code triggers aberrant AS in cancer. In addition, it highlights recent advances in programmable DNA-targeting technologies and their possible application for AS targeted epigenetic modulation.
选择性剪接（AS）是一种受严格调控的机制，它能从少数基因中产生复杂的人类蛋白质组。-外显子和内含子中的调控 RNA 基序控制 AS，招募正、负调节剪接因子。在更高的层次上，染色质影响剪接事件。越来越多的证据表明，流行的组蛋白密码假说可以扩展到 RNA 水平的过程，如 AS。除了核小体定位，它可以产生转录障碍来塑造最终的剪接结果外，组蛋白的翻译后修饰也可以有助于单个外显子包含/排除的精细调节。基于组蛋白的系统可以识别选择性剪接的染色质延伸，通过衔接复合物局部影响 RNAPII 延伸或招募剪接成分。在肿瘤细胞中，有几种机制触发失调的 AS 事件，并产生与癌症相关的转录本。在全基因组水平上，异常的 AS 可能是功能失调的表观遗传剪接密码的结果，包括组蛋白翻译后修饰的富集改变。这篇综述描述了与组蛋白修饰和变体对剪接结果的影响相关的主要发现，以及功能失调的表观遗传剪接密码如何触发癌症中的异常 AS。此外，它还强调了可编程 DNA 靶向技术的最新进展及其在 AS 靶向表观遗传调节中的可能应用。
