Molecular effects of dADD1 misexpression in chromatin organization and transcription

Silvia Meyer-Nava,Mario Zurita,Amada Torres,Viviana Valadez-Graham

doi:10.1186/s12860-020-00257-2

Silvia Meyer-Nava, Mario Zurita + Show 2 more

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https://doi.org/10.1186/s12860-020-00257-2

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Abstract

BackgrounddADD1 and dXNP proteins are the orthologs in Drosophila melanogaster of the ADD and SNF2 domains, respectively, of the ATRX vertebrate’s chromatin remodeler, they suppress position effect variegation phenotypes and participate in heterochromatin maintenance.ResultsWe performed a search in human cancer databases and found that ATRX protein levels were elevated in more than 4.4% of the samples analyzed. Using the Drosophila model, we addressed the effects of over and under-expression of dADD1 proteins in polytene cells. Elevated levels of dADD1 in fly tissues caused different phenotypes, such as chromocenter disruption and loss of banding pattern at the chromosome arms. Analyses of the heterochromatin maintenance protein HP1a, the dXNP ATPase and the histone post-translational modification H3K9me3 revealed changes in their chromatin localization accompanied by mild transcriptional defects of genes embedded in heterochromatic regions. Furthermore, the expression of heterochromatin embedded genes in null dadd1 organisms is lower than in the wild-type conditions.ConclusionThese data indicate that dADD1 overexpression induces chromatin changes, probably affecting the stoichiometry of HP1a containing complexes that lead to transcriptional and architectural changes. Our results place dADD1 proteins as important players in the maintenance of chromatin architecture and heterochromatic gene expression.

Highlights

DADD1 and Drosophila X-linked Nuclear Protein (dXNP) proteins are the orthologs in Drosophila melanogaster of the ADD and SNF2 domains, respectively, of the Alpha-thalassemia and Mental Retardation X-related (ATRX) vertebrate’s chromatin remodeler, they suppress position effect variegation phenotypes and participate in heterochromatin maintenance
ATRX expression levels in human cancers Mutations that affect the function of ATRX have been associated with several types of cancers, including glioblastoma and pancreatic cancer [20, 21] and ATRX aberrant expression has been recently proposed as a marker of poor survival in soft tissue sarcomas [8]
This search found that ATRX is expressed in all types of cells reviewed on THPA database with high TPM (Transcripts Per Million) values, principally in tissues like parathyroid and thyroid glands, cerebral cortex and endometrium, the thresholds used to categorize over- and under-expression from normal levels is explained in the database

Summary

Introduction

DADD1 and dXNP proteins are the orthologs in Drosophila melanogaster of the ADD and SNF2 domains, respectively, of the ATRX vertebrate’s chromatin remodeler, they suppress position effect variegation phenotypes and participate in heterochromatin maintenance. The major factors involved in chromatin dynamics are ATP-dependent chromatin remodeling complexes, which contain an ATPase catalytic subunit, which provides the energy necessary for their function One of these ATPases is ATRX, first described as a putative member of the helicase superfamily due to its homology with RAD54 that has been implicated in nucleotide excision repair and transcription [1, 2]. The human mutations usually generate a change in protein functionality and mostly fall into the helicase-ATPase domain in the carboxy terminus, or the ADD motif (named after the three proteins that carry it, ATRXDNMT3-DNMT3L), composed of a PHD and a GATAlike zinc fingers, which recognize the H3K9me and the unmethylated H3K4 combination of histone marks [5]. There has been described that the ATRX PxVxL motif can target ATRX through HP1a, and mutations in this motif [7] reduce the localization of ATRX in the heterochromatin [6]

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