DYRK1A interacts with histone acetyl transferase p300 and CBP and localizes to enhancers

Abstract

DYRK1A, dual-specificity tyrosine phosphorylation-regulated kinase 1A, which is linked to mental retardation and microcephaly, is a member of the CMGC group of kinases. It has both cytoplasmic and nuclear functions, however, molecular mechanisms of how DYRK1A regulates gene expression is not well understood. Here, we identify two histone acetyltransferases, p300 and CBP, as interaction partners of DYRK1A through a proteomics study. We show that overexpression of DYKR1A causes hyperphosphorylation of p300 and CBP. Using genome-wide location (ChIP-sequencing) analysis of DYRK1A, we show that most of the DYRK1A peaks co-localize with p300 and CBP, at enhancers or near the transcription start sites (TSS). Modulation of DYRK1A, by shRNA mediated reduction or transfection mediated overexpression, leads to alteration of expression of downstream located genes. We show that the knockdown of DYRK1A results in a significant loss of H3K27acetylation at these enhancers, suggesting that DYRK1A modulates the activity of p300/CBP at these enhancers. We propose that DYRK1A functions in enhancer regulation by interacting with p300/CBP and modulating their activity. Overall, DYRK1A function in the regulation of enhancer activity provides a new mechanistic understanding of DYRK1A mediated regulation of gene expression, which may help in better understanding of the roles of DYRK1A in human pathologies.

A complex between DYRK1A and DCAF7 phosphorylates the C-terminal domain of RNA polymerase II to promote myogenesis

“…Indeed, the lack of a distinctive and prominent DYRK1A enrichment peak at the MYH2 promoter (Figure 6F-I), the co-localization of DYRK1A–DCAF7 with Pol II across the MYH2 gene locus (Figure 6F-I), and the dependence on DCAF7 for DYRK1A to occupy the three myogenic gene loci (Figure 6C) agree with the model that the association of DYRK1A with the three genes is mediated by the binding of DCAF7 to the elongating Pol II. The idea that DYRK1A may use different gene-targeting modes to regulate transcription in different cell types and/or in response to distinct signals is further supported by a very recent study showing that DYRK1A interacts with histone acetyl transferases P300 and CBP to localize to gene enhancers and influence transcription in T98G cells (36).…”

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

“…DYRK1A proteins were visualized using mouse anti[FLAG antibody (1:1:000; Sigma Aldrich, #F1804), and their level normalized with EGFP (in[house mouse anti[GFP antibody). Immunofluorescence experiments were performed in HeLa cells as previously done (Mattioli et al, 2018), and fluorescence was visualized on an inverted confocal microscope (SP2UV, Leica, Wetzlar, Germany). For autophosphorylation analysis, proteins were extracted from HEK293 cells transfected with DYRK1A plasmids and immunoprecipitated with anti-FLAG antibody as described (Mattioli et al, 2018) with the addition of a phosphatase inhibitor cocktail 2 (Sigma Aldrich).…”

“…DNAm signatures are highly sensitive and specific for each condition, able to discriminate between related disorders, and useful for classifying variants in these genes as pathogenic or benign (Choufani et al , 2015; Butcher et al , 2017; Aref-Eshghi et al , 2019; Chater-Diehl et al , 2019). DYRK1A has numerous targets, and while it is not well described as an epigenetic regulator, it has been shown to phosphorylate Histone H3 (Jang et al , 2014) as well proteins with acetyltransferase activity such as CBP and p300 (Li et al , 2018). Therefore, we hypothesized that pathogenic variants in DYRK1A would be associated with a specific DNAm signature in blood.…”

DCAF7/WDR68 is required for normal levels of DYRK1A and DYRK1B

“…Likewise, DYRK1A overexpression can inhibit cell proliferation and induce premature neuronal differentiation by phosphorylating p27 kip1 and CYCLIN D1 [40]. DYRK1A also functions as a nuclear transcriptional co-activator via phosphorylation of the RNApII-CTD [41], and recruitment of histone acetyl transferases [42], to regulate a variety of genes implicated in cell cycle control.…”