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Fat Tissue Sequencing Leads to LincRNA With Ties to Obesity, Metabolism

NEW YORK (GenomeWeb) – A Columbia University-led team has uncovered long intergenic noncoding RNAs (lincRNAs) that appear to be specific to human fat tissue, and characterized one, linc-ADAL, that contributes to obesity-related regulatory processes.

The researchers initially tracked down more than 1,000 apparent lincRNAs through deep RNA sequencing analyses on gluteal subcutaneous adipose tissue samples — below-the-skin butt fat — from 25 healthy participants. A subset of 20 lincRNAs had enhanced expression in the adipose tissue compared to other tissue types, and nearly half of those appeared to be capable of binding transcription factors.

When the team took a closer look at the adipose tissue-specific lincRNA set, using samples from 22 formerly obese individuals before and after bariatric surgery, it saw expression shifts for 53 of the lincRNAs three months post surgery. Likewise, at least 49 of the lincRNAs seemed to be expressed differently in male and female participants.

"[I]n support of their physiological relevance, the expression of subsets of adipose lincRNAs is influenced by sex and race," senior author Muredach Reilly, a cardiology, clinical, and translational research investigator at Columbia University, and his co-authors wrote in a study published online today in Science Translational Medicine.

While the majority of those lincRNAs were not conserved in mice, their analyses on one of the most highly expressed representatives supports the notion that at least some members of the lincRNA set do contribute to obesity, fat cell differentiation, and de novo lipogenesis.

Such results "support the functional and potential clinical significance of recently evolved, noncoding regulatory elements in the human genome," the authors wrote.

The researchers sequenced the RNA of subcutaneous adipose tissue samples from 25 healthy, lean participants, mapping the reads to version hg19 of the human reference genome to annotate known and novel lincRNAs, which were assembled de novo.

After weeding out transcripts with more than one exon, potential protein-coding function, or aberrant expression, the team was left with 857 already annotated lincRNAs and 144 new candidate lincRNAs that were expressed in fat samples from all participants, including the 120 adipose-specific lincRNAs.

The researchers detected 60 percent of the lincRNAs in RNA-seq data for adipose samples from another 22 participants — a group of formerly obese individuals treated with bariatric surgery. Around 100 lincRNA-messenger RNA pairs showed expression shifts in these patients three months after surgery relative to their expression levels before surgery, including transcripts for genes related to fatty acid metabolism and fibrosis.

In a series of subsequent analyses, the team considered the tissue-specificity, conservation, transcriptional regulation, and other features of the lincRNA set. From the widespread lack of lincRNA conservation, for example, the group speculated that lincRNAs may have undergone relatively rapid evolution in human adipose tissue. 

The researchers performed more in-depth functional analyses on one of the most prevalent lincRNAs in adipose tissue, called linc-ADAL. In addition to identifying two transcript isoforms for it, they detected roles for linc-ADAL in processes such as adipocyte differentiation, de novo lipogenesis in adipocyte cells, and lipid metabolism.

Overall, the authors wrote, the new data "provide a unique resource for studying lincRNAs, particularly non-conserved ones, in human adipose biology, obesity, and related metabolic diseases."