How allelic asymmetry is generated remains a major unsolved problem in epigenetics. Here we model the problem using X-chromosome inactivation by developing “BioRBP”, an enzymatic RNA-proteomic method that enables probing of low-abundance interactions and an allelic RNA-depletion and -tagging system. We identify messenger RNA-decapping enzyme 1A (DCP1A) as a key regulator of Tsix, a noncoding RNA implicated in allelic choice through X-chromosome pairing. DCP1A controls Tsix half-life and transcription elongation. Depleting DCP1A causes accumulation of X–X pairs and perturbs the transition to monoallelic Tsix expression required for Xist upregulation. While ablating DCP1A causes hyperpairing, forcing Tsix degradation resolves pairing and enables Xist upregulation. We link pairing to allelic partitioning of CCCTC-binding factor (CTCF) and show that tethering DCP1A to one Tsix allele is sufficient to drive monoallelic Xist expression. Thus, DCP1A flips a bistable switch for the mutually exclusive determination of active and inactive Xs.

等位基因不对称性是如何产生的仍然是表观遗传学中尚未解决的主要问题。在这里，我们通过开发“BioRBP”使用 X 染色体失活来模拟问题，“BioRBP”是一种酶促 RNA 蛋白质组学方法，能够探测低丰度相互作用和等位基因 RNA 耗竭和标记系统。我们将信使 RNA 脱帽酶 1A (DCP1A) 鉴定为 Tsix 的关键调节因子，Tsix 是一种通过 X 染色体配对参与等位基因选择的非编码 RNA。DCP1A 控制 Tsix 半衰期和转录延伸。耗尽 DCP1A 会导致 X-X 对的积累，并扰乱向Xist上调所需的单等位基因 Tsix 表达的转变。虽然消融 DCP1A 会导致超配对，但强制 Tsix 降解会解决配对问题并启用Xist上调。我们将配对与 CCCTC 结合因子 (CTCF) 的等位基因分配联系起来，并表明将 DCP1A 拴在一个Tsix等位基因上足以驱动单等位基因Xist表达。因此，DCP1A 翻转双稳态开关以相互排斥确定活动和非活动 X。