2-hydroxyglutarate controls centromere and heterochromatin conformation and function in the male germline

2-hydroxyglutarate (2HG) is recognized as an epigenetic regulator in cancer and in a few physiological states. Of all organs, the testis harbors the highest levels of 2HG, yet it's putative functions in germ cell biology are unknown. Here we show that 2HG is generated in specific stages of the mouse germ cell lineage by the testis specific lactate dehydrogenase C (LDHC). LDHC is expressed in pachytene, diplotene and diakinesis (PDD) cells and unexpectedly enters nuclei where it localizes along chromosomes and centromeres. LDHC-generated L-2HG controls centromere compaction and pericentromeric heterochromatin organization through multiple effects including clustering of chromocenters, centromere and chromocenter condensation and expression of satellite RNAs. The involvement of L-2HG in the above functions was shown both in isolated PDD cells and in vivo and is specific to the L but not D enantiomer. Our findings reveal that 2HG can rapidly change the conformation of these multisubunit structures and is necessary for the proper progression of the cell cycle. ### Competing Interest Statement The authors have declared no competing interest.