Species-specific regulation of XIST by the JPX/FTX orthologs

Area of Science:

• Genetics
• Evolutionary Biology
• Developmental Biology

Background:

• X chromosome inactivation (XCI) is crucial for mammalian development but shows species-specific initiation.
• Long non-coding RNA genes (LRGs) are implicated in XCI regulation, with some co-evolving with XIST.
• Understanding the conservation of LRGs like FTX and JPX across species is key to deciphering XCI diversity.

Purpose of the Study:

• To investigate the functional conservation of human FTX and JPX orthologues in X chromosome inactivation (XCI).
• To compare the roles of FTX and JPX in human and mouse pluripotent stem cells and differentiated cells.
• To elucidate the evolutionary mechanisms underlying LRG function in gene regulatory networks.

Main Methods:

• Analysis of single-cell RNA-sequencing data from early human embryogenesis.
• Functional assays in matched human and mouse pluripotent stem cells.
• Functional assays in matched human and mouse differentiated post-XCI cells.

Main Results:

• Human FTX orthologue shows functional divergence compared to its mouse counterpart.
• Human and mouse JPX orthologues both regulate XIST expression, a key step in XCI.
• Species-specific mechanisms of JPX action on XIST production were identified, independent of sequence conservation.

Conclusions:

• Orthologous LRGs can exhibit significant functional differences across mammalian species.
• JPX plays a conserved role in XIST regulation, but employs diverse molecular strategies.
• The evolvability of LRGs provides adaptive flexibility to gene regulatory networks, contributing to developmental diversity.