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Gene, Long Non-Coding RNA Expression Shift During Organ Development

NEW YORK – The expression of protein-coding genes and long-noncoding RNAs shifts during organ development, according to two analyses of bulk transcriptome data from half a dozen species.

A Heidelberg University-led team examined gene expression in seven different organs during development, to find that organs from different species are the most similar early in development and then become more distinct. In particular, the researchers found that both protein-coding genes and lncRNAs are at first broadly expressed, but then become more organ and lineage-specific in their expression patterns later in development. 

The findings were reported in a pair of papers appearing in Nature today.

"The traits of the organs that characterize a species do not originate until later during development," senior author Henrik Kaessmann, a group leader at the Center for Molecular Biology of Heidelberg University, said in a statement.

"Using modern molecular methods, we were able for the first time to confirm a groundbreaking hypothesis in biology from the 19th century," he added, referring to the notion put forth by Karl Ernst von Baer that the earlier in development it is, the harder it is to tell mammalian embryos apart.

In the first paper, Kaessmann and his colleagues examined gene expression in seven different organs during development, from early organogenesis to adulthood, from seven animals. In particular, they generated bulk transcriptomes of the brains, cerebella, hearts, kidneys, ovaries and testes, and livers of six mammals — humans, rhesus macaques, mice, rats, rabbits, and opossums — and one bird, red junglefowl or chicken.

A principal component analysis of these transcriptomes found that they first grouped by the germ layer from which the organ is derived, followed by developmental stage and species.

Between 79 percent and 91 percent of protein-coding genes showed temporal differences in expression in each organ, the researchers reported. They additionally noted that in each species, between 6 percent and 15 percent of genes were developmentally dynamic genes in only one organ.

When they compared gene expression patterns across species, they found the similar genes were expressed in organs from different animals during corresponding developmental stages. Then as development progressed, the researchers noted an increase in the expression of organ-specific genes and a decrease in the expression of cell division and general morphogenesis genes.

At the individual gene level, they further found that the development trajectories sometimes varied across species. In particular, the brain exhibited the smallest number of trajectory changes — 11 percent — while the liver and the testis exhibited the highest — at 23 percent and 27 percent, respectively. 

Based on this, the researchers said they suspect that changes in pleiotropy contribute to organs becoming more distinct later in development.

Using the same transcriptomic dataset, the researchers also examined the developmental dynamics of long non-coding RNAs during organ development across species. From this, they identified between 15,000 and 35,000 candidate lncRNAs, representing about half of the human and mouse lncRNA and antisense transcripts from Ensembl as well as new lncRNAs. 

Most of these lncRNAs are species specific, the researchers noted. Further, unlike the protein-coding genes from the first paper, only a portion of lncRNAs exhibited developmentally dynamic expression.

But these developmentally dynamic lncRNAs, the researchers noted, are over-represented for proximity to protein-coding genes and are also longer and harbor more exons. They are also enriched for functional relevance. More than three-quarters of the developmentally dynamic lncRNAs are thought to have functional ramifications, and a CRISPR interference screen revealed a number of them are involved in cell proliferation.

As development progresses, the researchers found a shift from broadly expressed and conserved lncRNAs to ones that are increasingly lineage- and organ-specific — similar to the protein-coding genes.

This, the researchers noted, suggests that lncRNAs contribute to different stages of organ development.