Thursday, April 25, 2019

Long, non-coding RNA serve an important role in the regulatory pathway controlling human skin wound healing

It seems like there has been a lot of cool wound-healing research results published lately. At the end of March, there was the result that bacteriophages hide their bacterial hosts from being cleared by mammalian immune response. Last week there was the result that aphids soldier nymphs use their own wound-healing proteins to plug gall holes. And now there's this new result on the mechanism underlying the role of long, noncoding RNA (lncRNA) in wound healing of human skin.

So what's long, non-coding RNA? The DNA in the human genome has to be converted to RNA, in much the same way computer code might be converted into assembly language, before it can then be converted into proteins (like assembly language being converted into object code that can actually be executed by the computer). Up until recently, biology has focused entirely on this pipeline -- DNA to RNA to protein. However, there are some bits of DNA that stop at RNA, which are termed "non-coding RNA" because they don't end up producing any proteins. They just float around until they naturally break down. However, there are hints that they are not merely intermediate transitional objects and that they can be functional molecules themselves. One of those hints is that they can be consistently turned on ("up-regulated") in certain situations. However, this doesn't mean that they're actually doing anything. There are technical details that make it useful to distinguish whether these non-coding RNA are short or long. I won't get into those. Just know, for the reset of this post, that "lncRNA" represents "long, non-coding RNA", which is a type of these mysterious molecules. When healthy human skin is wounded, the normal response happens to involve the up-regulation of one of these lncRNA's is consistently generated more than in undamaged tissue, but no one knows why.

In this paper, they show that the molecule actually sequesters other mechanisms within the tissue that would normally turn off the migration of cells important for wound healing. So the lncRNA's are functional -- they get turned on when the skin is wounded, and that sets of a chain reaction that disables other mechanisms that would normally keep wound healing processes turned off. So the lncRNA's are an important step in the regulatory network. That's very cool. It not only helps scientists understand wound healing but also one more way in which lncRNA's can be functional -- not just junk molecules floating around waiting to be broken back down.

Here is the primary source:

"Human skin long noncoding RNA WAKMAR1 regulates wound healing by enhancing keratinocyte migration"
by Li et al.
PNAS (2019), early edition
https://doi.org/10.1073/pnas.1814097116

Significance
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Although constituting the majority of the transcriptional output of the human genome, the functional importance of long noncoding RNAs (lncRNAs) has only recently been recognized. The role of lncRNAs in wound healing is virtually unknown. Our study focused on a skin-specific lncRNA, termed “wound and keratinocyte migration-associated lncRNA 1” (WAKMAR1), which is down-regulated in wound-edge keratinocytes of human chronic nonhealing wounds compared with normal wounds under reepithelialization. We identified WAKMAR1 as being critical for keratinocyte migration and its deficiency as impairing wound reepithelialization. Mechanistically, WAKMAR1 interacts with DNA methyltransferases and interferes with the promoter methylation of the E2F1 gene, which is a key transcription factor controlling a network of migratory genes. This line of evidence demonstrates that lncRNAs play an essential role in human skin wound healing.
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Abstract
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An increasing number of studies reveal the importance of long noncoding RNAs (lncRNAs) in gene expression control underlying many physiological and pathological processes. However, their role in skin wound healing remains poorly understood. Our study focused on a skin-specific lncRNA, LOC105372576, whose expression was increased during physiological wound healing. In human nonhealing wounds, however, its level was significantly lower compared with normal wounds under reepithelialization. We characterized LOC105372576 as a nuclear-localized, RNAPII-transcribed, and polyadenylated lncRNA. In keratinocytes, its expression was induced by TGF-β signaling. Knockdown of LOC105372576 and activation of its endogenous transcription, respectively, reduced and increased the motility of keratinocytes and reepithelialization of human ex vivo skin wounds. Therefore, LOC105372576 was termed “wound and keratinocyte migration-associated lncRNA 1” (WAKMAR1). Further study revealed that WAKMAR1 regulated a network of protein-coding genes important for cell migration, most of which were under the control of transcription factor E2F1. Mechanistically, WAKMAR1 enhanced E2F1 expression by interfering with E2F1 promoter methylation through the sequestration of DNA methyltransferases. Collectively, we have identified a lncRNA important for keratinocyte migration, whose deficiency may be involved in the pathogenesis of chronic wounds.
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