Post-transcriptional regulation (PTR) of gene expression is a powerful determinant of cellular phenotypes. The 5′ and 3′ untranslated regions of the mRNA (UTRs) mediate this role through sequence and secondary structure elements bound by RNA-binding proteins (RBPs) and non-coding RNAs. While functional regions in the 3′UTRs have been extensively studied, the 5′UTRs are still relatively uncharacterized. To fill this gap, we used a computational approach exploiting phylogenetic conservation to identify hyperconserved elements in human 5′UTRs (5′HCEs). Our assumption was that 5′HCEs would represent evolutionarily stable and hence important PTR sites. We identified over 5000 5′HCEs occurring in 10% of human protein-coding genes. These sequence elements are rather short and mostly found in narrowly-spaced clusters. 5′HCEs-containing genes are enriched in essential cellular functions and include 20% of all homeotic genes. Homeotic genes are essential transcriptional regulators, driving body plan and neuromuscular development. However, the role of PTR in their expression is mostly unknown. By integrating computational and experimental approaches we identified RBMX as the initiator RBP of a post-transcriptional cascade regulating many homeotic genes. This work thus establishes 5′HCEs as mediators of essential post-transcriptional regulatory networks.

基因表达的转录后调控（PTR）是细胞表型的有力决定因素。mRNA（UTR）的5'和3'非翻译区通过由RNA结合蛋白（RBP）和非编码RNA结合的序列和二级结构元件来介导此作用。尽管已经对3'UTR中的功能区域进行了广泛研究，但5'UTR仍未表征。为了填补这一空白，我们使用了一种系统发育保护的计算方法来鉴定人5'UTR（5'HCE）中的超保守元件。我们的假设是5'HCEs代表进化稳定的重要PTR位点。我们鉴定出超过5000个5'HCE发生在10％的人类蛋白质编码基因中。这些序列元素相当短，并且大多位于狭窄的簇中。含有5'HCEs的基因丰富了必需的细胞功能，并包括所有同源基因的20％。同源基因是必需的转录调节因子，可驱动身体计划和神经肌肉发育。但是，PTR在其表达中的作用大多是未知的。通过整合计算和实验方法，我们确定了RBMX是调控许多同源基因的转录后级联的起始RBP。因此，这项工作建立了5'HCE作为重要的转录后调控网络的媒介。通过整合计算和实验方法，我们确定了RBMX是调控许多同源基因的转录后级联的起始RBP。因此，这项工作建立了5'HCE作为重要的转录后调控网络的媒介。通过整合计算和实验方法，我们确定了RBMX是调控许多同源基因的转录后级联的起始RBP。因此，这项工作建立了5'HCEs作为基本转录后调控网络的媒介。