Human pluripotent stem cells are one of the key sources investigated worldwide in the search of the proverbial ‘fountain of youth’ given that every tissue/organ in the body arises from them. By mimicking the signals in a developing embryo in a dish, pluripotent stem cells can be coaxed into activating the genetic networks instructing them to differentiate into functional human cells, which have unlimited therapeutic potential.
Realizing this potential, multiple clinical studies are currently under way including cell replacement therapies to improve life-quality in aged individuals. However, our understanding of the genetic networks that control the differentiation processes that lead to the generation of functional human cell types during embryonic development is far from complete. Comprehensive insights on the key genetic determinants of cell-fate decisions and their hierarchy during differentiation is pivotal in understanding embryonic development and to ensure the advancement of safe approaches to generate mature, functional cells for cell-replacement therapies.
Dr. Leo Kurian, heading a NRW Stem Cell Network Junior Research Group at the CMMC, and his team identified and defined a currently unknown class of genes called ying yang lncRNAs (yylncRNA). They demonstrated that this developmentally specialized class of genes, that lack the ability to code for proteins, is organized in the mammalian genome in a head to head fashion with key regulators of embryonic development.
Indicating the central role of yylncRNAs in regulating cell fate decisions, they report the molecular and functional importance of yylncT, a yylncRNA encoded from the BRACHYURY (T) locus. BRACHYURY is the master regulator of mesoderm development, the lineage that gives rise to organs including the heart, vasculature and skeletal muscles (tissue types that are severely affected by aging).
Stefan Frank, Deniz Bartsch and Gaurav Ahuja, sharing first authorship of the study, comment: “Our data indicate that yylncT is essential for mesoderm differentiation of human pluripotent stem cells. It acts as a gatekeeper of the genetic locus that encodes BRACHYURY. In the absence of yylncT, human pluripotent stem cells fail to acquire mesoderm fate leading to a molecular collapse resulting in their apoptosis. Mechanistically, yylncT defends the yylncT/T locus from unwanted DNA methylation of this locus by directly binding to the de novo DNA methyltransferase, DNMT3B, and inhibiting its function locally".
De novo DNA methylation facilitates the stabilization of cellular identities during embryogenesis, while loci encoding regulators of developmental cell fate decisions remain hypomethylated. “Our research reveals a long non-coding RNA mediated regulatory layer essential for safeguarding these loci from aberrant DNA methylation”, Leo Kurian comments.
This study is detailed in Cell Stem Cell on December 13, 2018. [Epub ahead of print]
Link : https://www.cell.com/cell-stem-cell/fulltext/S1934-5909 (18)30541-1
Frank S*, Ahuja G*, Bartsch D*, Russ N, Yao W, Kuo JC, Derks JP, Akhade VS, Kargapolova Y, Georgomanolis T, Messling JE, Gramm M, Brant L, Rehimi R, Vargas NE, Kuroczik A, Yang TP, Sahito RGA, Franzen J, Hescheler J, Sachinidis A, Peifer M, Rada-Iglesias A, Kanduri M, Costa IG, Kanduri C, Papantonis A, Kurian L.
* joinded first autorship
The Kurian lab is supported by the NRW Stem Cell Network Independent Group Leader Grant, CMMC, German Heart Association (DZHK), Else Kröner-Fresenius Stiftung (EKFS), Deutsche Forschungsgemeinschaft (DFG) and University of Cologne.