Chromatin-modifying enzymes as modulators of nuclear size during lineage differentiation

Abstract

AbstractThe mechanism of nuclear size determination and alteration during normal lineage development and cancer pathologies which is not fully understood. As recently reported, chromatin modification can change nuclear morphology. Therefore, we screened a range of pharmacological chemical compounds that impact the activity of chromatin-modifying enzymes, in order to get a clue of the specific types of chromatin-modifying enzymes that remarkably effect nuclear size and shape. We found that interrupted activity of chromatin-modifying enzymes is associated with nuclear shape abnormalities. Furthermore, the activity of chromatin-modifying enzymes perturbs cell fate determination in cellular maintenance and lineage commitment. Our results indicated that chromatin-modifying enzyme regulates cell fate decision during lineage differentiation and is associate with nuclear size alteration.SignificanceHere we described for the first time the modulation of chromatin-modifying enzymes remarkably effects nuclear shape, and perturbs cell fate determination in cellular maintenance and lineage fate commitment in normal stem cells and leukemia cancer cells. We found that the irregularities of nuclear contour were highly related to pharmacological inhibition of chromatin-modifying enzyme activity. After manipulating a histone demethylase named GASC1, we found that upregulation of GASC1 impairs the differentiation of hESCs to terminally differentiated neural cells. Moreover, upregulation of GASC1 impairs the proliferation of leukemia cells due to cell cycle arrest in the G0/G1 phase and indicates misshapen nuclei. This study suggested that chromatin-modifying enzyme regulates the nuclear contour related cell fate decision also including cancer cell fate determination.