A Chromatin Checkpoint Links mRNA Quality Control To Transcriptional Regulation [RNA-seq]

Eukaryotic mRNAs undergo premature transcriptional termination and degradation to prevent aberrant expression of protein coding genes. mRNAs are subjected to co-transcriptional RNA surveillance and non-canonical transcriptional termination similar to non-coding RNAs. The Nrd1-Nab3-Sen1 (NNS) RNA binding complex and the nuclear exosome complex containing the 3’-5’ RNA exonuclease Rrp6 contribute to mRNA quality control, resulting in attenuation of transcription of protein coding genes. mRNA transcriptional attenuation is particularly pronounced during the early steps of transcriptional elongation by RNA Polymerase II. However, the mechanisms regulating premature mRNA termination remain poorly understood. Moreover, the extent to which transcriptional attenuation contributes to the production of functional mRNAs is unclear. Here we show that, in yeast, the evolutionary conserved ATP-dependent chromatin remodelling complex INO80 promotes the removal of aberrant native mRNA transcripts from chromatin to enable transcription elongation. Loss of INO80 leads to genome-wide accumulation of early terminated, nascent mRNAs at DNA contact sites for the histone H3 N-terminal tail proximally to promoters, abrogating productive transcription. INO80 interacts with Nrd1 and promotes RNA decay by facilitating non-canonical transcription termination. Retention of native mRNAs at promoter proximal sites is regulated by the Rpd3S Histone Deacetylation complex. Chromatin relaxation by disruption of Rpd3S at a site of non-canonical transcriptional termination rescues the defect in productive transcription of functional mRNAs caused by disruption of INO80. Our work reveals how chromatin organisation controls transcriptional attenuation to regulate productive gene expression.真核信使RNA（messenger RNA, mRNA）会发生提前转录终止与降解，以避免蛋白编码基因出现异常表达。mRNA会经历共转录RNA监视过程，以及类似非编码RNA的非经典转录终止事件。Nrd1-Nab3-Sen1（NNS）RNA结合复合物与包含3’-5’ RNA外切核酸酶Rrp6的核外切体复合物共同参与mRNA质量控制，进而引发蛋白编码基因的转录衰减。RNA聚合酶II（RNA Polymerase II）在转录延伸的早期阶段，mRNA转录衰减现象尤为显著。然而，调控mRNA提前终止的具体分子机制仍不甚明确。此外，转录衰减在多大程度上影响功能性mRNA的生成，目前也尚未明晰。本研究以酵母为模型，证实进化保守的ATP依赖型染色质重塑复合物INO80可促进异常天然mRNA转录本从染色质上解离，以保障转录延伸顺利进行。INO80功能缺失会导致全基因组范围内，启动子近端的组蛋白H3 N端尾DNA结合位点处，提前终止的新生mRNA发生富集，从而阻断有效转录过程。INO80可与Nrd1相互作用，并通过促进非经典转录终止加速RNA降解。天然mRNA在启动子近端区域的滞留，受到Rpd3S组蛋白去乙酰化复合物的调控。在非经典转录终止位点处，通过破坏Rpd3S功能实现染色质松弛，可挽救因INO80功能缺失导致的功能性mRNA有效转录缺陷。本研究揭示了染色质组织如何通过调控转录衰减，进而影响基因的有效表达。