RNA catabolism restricts ERV expression and functionalization [EU-RNA-Seq]

Endogenous retroviruses (ERVs) are remnants of ancient parasitic viral integrations and comprise a sizable portion of the genome in most organisms. Deregulated expression of ERVs in human is associated with a plethora of disease conditions, such as cancer and neurodegeneration. Epigenetic mechanisms silence most ERVs by generating a local repressive environment (heterochromatin) to prevent their expression. However, the mechanisms controlling the fate of ERVs residing in euchromatic regions of the genome (e.g. MERVL elements) are not well understood. Here, by integrating multidimensional epigenetic and genomic analyses, we demonstrate that silencing of euchromatic MERVL elements is achieved via transcription-coupled RNA degradation. Disrupting RNA catabolism promotes RNAPII elongation from MERVL promoters, increases MERVL expression and exonization, creating novel chimeric gene isoforms, and directing embryonic stem (ES) cells toward a terminal undifferentiated state. Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards cell identity and potency, restricts MERVL functionalization and suppresses gene birth. EU-Seq of WT and Exosc3 cKO mESCs, including total and labeled (10min) RNA samples each. N=2 replicates per condition, 8 samples total.

内源性逆转录病毒（Endogenous retroviruses, ERVs）是远古寄生病毒整合事件遗留的基因组片段，在多数生物的基因组中占比可观。人体内源性逆转录病毒的表达失调与多种疾病状态密切相关，例如癌症与神经退行性病变。表观遗传机制通过构建局部抑制性微环境（异染色质，heterochromatin）沉默绝大多数内源性逆转录病毒的表达。然而，对于位于基因组常染色质区域的内源性逆转录病毒（如MERVL元件）的命运调控机制，目前尚不清楚。本研究通过整合多维度表观遗传与基因组分析手段，证实常染色质区域的MERVL元件的沉默通过转录偶联RNA降解途径实现。阻断RNA代谢（RNA catabolism）会促进RNA聚合酶II（RNA polymerase II, RNAPII）从MERVL启动子处延伸，上调MERVL的表达与外显子化（exonization）过程，进而产生全新的嵌合基因剪接变体（chimeric gene isoforms），并将胚胎干细胞（embryonic stem cells, ES细胞）导向终末未分化状态。本研究结果表明，RNA代谢是基因调控网络的核心调控模块，能够维持细胞身份与分化潜能，限制MERVL元件的功能化进程，并抑制新基因的诞生。本研究包含野生型（wild type, WT）与Exosc3条件性敲除（Exosc3 conditional knockout, Exosc3 cKO）小鼠胚胎干细胞（mouse embryonic stem cells, mESCs）的EU-seq测序数据，每个组别均包含总RNA与10分钟标记的RNA样本；每个条件设置2次生物学重复，总计8个样本。