EPB41L4A-AS1long noncoding RNA acts in bothcis- andtrans-acting transcriptional regulation and controls nucleolar biology

Mammalian genomes are pervasively transcribed into long noncoding RNAs (lncRNAs), whose functions and modes of action remain poorly understood.EPB41L4A-AS1is an evolutionary conserved, broadly and highly expressed lncRNA that produces the H/ACA snoRNASNORA13from one of its introns. We studied the consequences ofEPB41L4A-AS1perturbation in breast cancer cells and found that it acts bothin cis, to enhance transcription of the proximalEPB41L4Agene and additional genes in its two flanking topologically associated domains, and intransby broadly regulating gene expression, including expression of snoRNAs, transcription of genes involved in nucleolar biology and the distribution of nucleolar proteins. These effects are phenocopied by the loss of SUB1, an interactor ofEPB41L4A-AS1, and are observed following transient perturbations ofEPB41L4A-AS1that do not affect steady-stateSNORA13levels or the rRNA modification it helps install. Exogenous expression of the full-lengthEPB41L4A-AS1locus but notSNORA13expression can rescue thetrans-acting transcriptional effects of its perturbation. TheEPB41L4A-AS1gene is thus a versatile locus producing RNA molecules acting on multiple levels for key cellular functions.