The histone demethylase Kdm6b regulates a mature gene expression program in differentiating cerebellar granule neurons

Abstract

The histone H3 lysine 27 (H3K27) demethylase Kdm6b (Jmjd3) can promote cellular differentiation, however its physiological functions in neurons remain to be fully determined. We studied the expression and function of Kdm6b in differentiating granule neurons of the developing postnatal mouse cerebellum. At postnatal day 7, Kdm6b is expressed throughout the layers of the developing cerebellar cortex, but its expression is upregulated in newborn cerebellar granule neurons (CGNs). Atoh1-Cre mediated conditional knockout of Kdm6b in CGN precursors either alone or in combination with Kdm6a did not disturb the gross morphological development of the cerebellum. Furthermore, RNAi-mediated knockdown of Kdm6b in cultured CGN precursors did not alter the induced expression of early neuronal marker genes upon cell cycle exit. By contrast, knockdown of Kdm6b significantly impaired the induction of a mature neuronal gene expression program, which includes gene products required for functional synapse maturation. Loss of Kdm6b also impaired the ability of Brain-Derived Neurotrophic Factor (BDNF) to induce expression of Grin2c and Tiam1 in maturing CGNs. Taken together, these data reveal a previously unknown role for Kdm6b in the postmitotic stages of CGN maturation and suggest that Kdm6b may work, at least in part, by a transcriptional mechanism that promotes gene sensitivity to regulation by BDNF.

Dysregulation of the histone demethylase KDM6B in alcohol dependence is associated with epigenetic regulation of inflammatory signaling pathways

“…The majority of KDM6B studies have demonstrated a pivotal role for this enzyme in modulation of macrophage inflammatory responses 49 . Comparatively little is known about the role of KDM6B in the brain besides a handful of studies showing its involvement in neuronal differentiation and survival 50–51 . According to FACS analyses from rodent brain, 52–53 including publicly available RNA‐sequencing data 53–54 (data accessible at NCBI GEO database, accession number GSE52564 55 ), KDM6B is significantly enriched (greater than twofold increase) in microglia (one‐way ANOVA: F 6,13 = 11.89, P = .0023, n = 2) (Figure 4A).…”

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory

“…Regarding cocaine withdrawal, future CHIP assay might reveal this possibility. Alternatively, a previous study also reported that KDM6B may partly promote NMDA receptor gene expression by regulating BDNF (Wijayatunge et al , 2018). Therefore, H3K27me3 may target other genes to indirectly modulate NR2A expression and function by affecting NR2A protein synthesis/ degradation and/or phosphorylation.…”

Adolescent Alcohol Exposure Epigenetically Suppresses Amygdala Arc Enhancer RNA Expression to Confer Adult Anxiety Susceptibility

“…These results suggest the possibility that Arc eRNA expression may be sensitive to Kdm6b reduction whereas reductions in other synaptic genes lacking activitydependent enhancers may require changes in additional epigenetic regulators. KDM6B may lie downstream of BDNF action, as loss of KDM6B prevents BDNF-induced gene induction in cerebellar granule neurons (CGNs) (44). Importantly, several other genes involved in synaptic plasticity are also decreased, possibly due to globally condensed chromatin architecture in the amygdala after AIE.…”

“…*p<0.05, **p<0.01, ***p<0.001 by two-way ANOVA [Arc mRNA levels, AIE treatment (F 1,20 =12.6, p<0.01), acute alcohol exposure (F 1,20 =17.8, p<0.001); Arc eRNA (+), AIE exposure (F 1,20 =4.93, p<0.05), acute alcohol exposure (F 1,20 =47.3, p<0.001); Arc eRNA (−), acute alcohol exposure (F 1,19 =35.0, p<0.001), interaction between AIE treatment and acute alcohol exposure (F 1,19 =4. 44 AIE produces long-lasting impacts on epigenetic reprogramming and decreases synapserelated transcriptional events in the amygdala leading to anxiety-like behaviors in adulthood. AIE increases the repressive epigenetic mark H3K27 trimethylation (H3K27me3) and decreases lysine demethylase 6B (KDM6B), CREB binding protein (CBP), and H3K27 acetylation (H3K27ac) at the Arc promoter and SARE site.…”