182 ΔNp63-mediated repression of the lncRNA NEAT1 modulates epidermal differentiation

The transcription factor ΔNp63, a master regulator of epithelial biology, is involved in regulating epithelial stem cell function and maintaining the integrity of stratified epithelial tissues such as the epidermis. To this end, ΔNp63 acts as transcriptional repressor or activator towards a distinct subset of protein-coding genes and microRNAs. However, how and whether ΔNp63 regulates long non-coding RNA (lncRNAs) expression is not known. Here, we identified the lncRNAs NEAT1 as a bona fide ΔNp63 transcriptional target. We found that in proliferating human keratinocytes ΔNp63 represses NEAT1 expression by recruiting the histone deacetylates HDAC1/HDAC2 to the p63 DNA binding site located in the proximal promoter of NEAT1 genomic locus. Upon induction of differentiation, ΔNp63 down-regulation is associated by a marked increase of NEAT1 RNA levels, resulting in an increased assembly of paraspeckles foci both in vitro and in human skin tissues. RNA-seq analysis associated with global DNA binding profile (ChIRP-seq) revealed that NEAT1 associates with the promoter of key epithelial transcription factors sustaining their expression during epidermal differentiation. These molecular events might explain the inability of NEAT1-depleted keratinocytes to undergo the correct epidermal differentiation program. Remarkably, NEAT1 expression is dysregulated in those skin pathologies characterized by aberrant proliferation/differentiation switch such as ichthyosis and psoriasis, suggesting its potential involvement in the pathogenesis of skin disorders.