Scientists reveal a progressive modification mode of heterochromatin relaxation by kinase

Compared with somatic cells, pluripotent stem cells have an open chromatin state and less heterochromatin. The transition between heterochromatin and euchromatin is the key in cell fate determination, including somatic cell reprogramming. The success of iPSCs induction requires chromatin remodeling, and is an ideal model to study epigenetic regulation. By using the iPS model, we and others have found that the cytoplasmic signals are involved in the regulation of histone and DNA modification in nucleus. However, the role of kinase mediated phosphorylation signal, which is the most important signal of cell response to extracellular environment, in chromatin remodeling and histone modification remains unclear. 

In a study published in Cell Death & Differentiation, PEI Duanqing’s and LIU Xingguo’s groups from Guangzhou Institutes of Biomedicine and Health identified mitogen-activated protein kinase kinase 6 (Mkk6) as a chromatin relaxer that can open heterochromatin. In the classical MAPK signaling pathway, Mkk6 phosphorylates and activates the downstream target P38 MAPK. However, the researchers found that Mkk6 loosens heterochromatin not via P38, but a novel target Gatad2b, a component of the repressive MeCP1-Mi-2/nucleosome remodeling and deacetylase (NuRD) complex, screened out by phosphorylated proteomics. 

Furthermore, the researchers showed that Mkk6 loosens heterochromatin and promotes histone acetylation through phosphorylating Gatad2b at S487 and T490 during reprogramming, in turn, leading to the enhanced binding ability of Sox2 and Klf4 and pluripotency genes expression. 

MAPK pathways receive a variety of extracellular stimuli and play critical roles in many biological responses such as cell growth and apoptosis, and in the classical kinase signaling pathways, the signal is transmitted through protein phosphorylation. In this study, signal was able to be progressively transferred from protein phosphorylation to protein acetylation. This study reveals an Mkk phosphorylation mediated modulation of chromatin status in reprogramming and elucidates a new signaling pathway between extracellular stimuli and intracellular gene expression that can be progressive transmitted from protein phosphorylation to acetylation. 

Scheme of Mkk3/6 enhancing reprogramming through Gatad2b-Phosphorylation Dependent Heterochromatin Loosening. Image by CHEN Keshi.