The Role of Long Non-Coding RNAs in Human Endoderm Differentiation

Abstract

The human genome sequencing revealed a vast complexity of transcripts, with over 80% of the genome being transcribed into non-coding RNAs. In particular, long non-coding RNAs (lncRNAs) have emerged as critical regulators of various cellular processes, including embryonic development and stem cell differentiation. Despite extensive efforts to identify and characterize lncRNAs, defining their mechanisms of action in state-specific cellular contexts remains a significant challenge. Only recently has the involvement of lncRNAs in human endoderm differentiation of pluripotent stem cells begun to be addressed, creating an opportunity to explore the mechanisms by which lncRNAs exert their functions in germ layer formation, lineage specification, and commitment. This review summarizes current findings on the roles of lncRNAs in endoderm differentiation, highlighting the functional mechanisms and regulatory aspects underlying their involvement in cell fate decisions leading to endoderm development. The key lncRNAs implicated in endoderm differentiation are discussed, along with their interaction with transcription factors and RNA-binding proteins and modulation of signaling pathways essential for endoderm development. Gaining insight into the regulatory roles of lncRNAs in endoderm differentiation enhances the understanding of developmental biology and provides a foundation for discovering novel lncRNAs involved in cell fate determination.

Keywords: human endoderm differentiation; lncRNAs; stem cells.

Figure 1

lncRNAs and their mechanism of action in endoderm differentiation of hiPSCs. GATA6-AS1 and T-REX17 are expressed in the nucleus of endoderm cells, while HIDEN is found in the cytoplasm. With different mechanisms of action, GATA6-AS1 functions in cis during endoderm differentiation by facilitating SMAD2/3 recruiting and binding to the GATA6 promoter, leading to its activation. T-REX17, on the other hand, is transcribed with the same topologically associated domain as SOX17 but does not regulate this transcription factor, implying a trans-acting role in differentiation through its interaction with heterogeneous ribonucleoprotein (hnRNP), particularly hnRNPU. HIDEN, first desert lncRNA associated with endoderm differentiation, physically interacts with IMP1 protein and enhances the stability of FZD5 by mediating the interaction between IMP1 and FZD5 mRNA.