Dosage compensation

About: Dosage compensation is a research topic. Over the lifetime, 1920 publications have been published within this topic receiving 124589 citations.

Varying levels of X chromosome coalescence in female somatic cells alters the balance of X-linked dosage compensation and is implicated in female-dominant systemic lupus erythematosus.

Abstract: The three-dimensional organization of the genome in mammalian interphase nuclei is intrinsically linked to the regulation of gene expression. Whole chromosome territories and their encoded gene loci occupy preferential positions within the nucleus that changes according to the expression profile of a given cell lineage or stage. To further illuminate the relationship between chromosome organization, epigenetic environment, and gene expression, here we examine the functional organization of chromosome X and corresponding X-linked genes in a variety of healthy human and disease state X diploid (XX) cells. We observe high frequencies of homologous chromosome X colocalization (or coalescence), typically associated with initiation of X-chromosome inactivation, occurring in XX cells outside of early embryogenesis. Moreover, during chromosome X coalescence significant changes in Xist, H3K27me3, and X-linked gene expression occur, suggesting the potential exchange of gene regulatory information between the active and inactive X chromosomes. We also observe significant differences in chromosome X coalescence in disease-implicated lymphocytes isolated from systemic lupus erythematosus (SLE) patients compared to healthy controls. These results demonstrate that X chromosomes can functionally interact outside of embryogenesis when X inactivation is initiated and suggest a potential gene regulatory mechanism aberration underlying the increased frequency of autoimmunity in XX individuals.

The genome-wide transcriptional consequences of the nullisomic-tetrasomic stocks for homoeologous group 7 in bread wheat.

Abstract: Hexaploid bread wheat (Triticum aestivum L) arose by two polyploidisation events from three diploid species with homoeologous genomes. Nullisomic-tetrasomic (nulli-tetra or NT) lines are aneuploid wheat plants lacking two and adding two of six homoeologous chromosomes. These plants can grow normally, but with significantly morphological variations because the adding two chromosomes or the remaining four chromosomes compensate for those absent. Despite these interesting phenomena, detailed molecular mechanisms underlying dosage deletion and compensation in these useful genetic materials have not been determined. By sequencing the transcriptomes of leaves in two-week-old seedlings, we showed that the profiles of differentially expressed genes between NT stocks for homoeologous group 7 and the parent hexaploid Chinese Spring (CS) occurred throughout the whole genome with a subgenome and chromosome preference. The deletion effect of nulli-chromosomes was compensated partly by the tetra-chromosomes via the dose level of expressed genes, according to the types of homoeologous genes. The functions of differentially regulated genes primarily focused on carbon metabolic process, photosynthesis process, hormone metabolism, and responding to stimulus, and etc., which might be related to the defective phenotypes that included reductions in plant height, flag leaf length, spikelet number, and kernels per spike. The perturbation of the expression levels of transcriptional genes among the NT stocks for homoeologous group 7 demonstrated the gene dosage effect of the subgenome at the genome-wide level. The gene dosage deletion and compensation can be used as a model to elucidate the functions of the subgenomes in modern polyploid plants.

Targeting of proteins to chromatin in Drosophila melanogaster

Abstract: Dosage compensation of sex chromosomes in Drosophila melanogaster is an excellent model system to study various aspects of targeting of protein factors to chromatin. Dosage compensation prevents male lethality by up regulating transcription from the single male X chromosome in the ~2 fold range to match the two active X chromosomes in females [reviewed in e.g. (Ferrari et al., 2014; Kuroda et al., 2016; Samata and Akhtar, 2018)]. This up regulation is facilitated by the male specific lethal (MSL) dosage compensation complex (DCC). The DCC binds selectively to ~300 high affinity sites (HAS) on the X chromosome, containing a low complexity GAGA rich sequence motif, the MSL recognition element (MRE) (Alekseyenko et al., 2008; Straub et al., 2008). However, the DCC neglects thousands of other similar sequences in the genome outside of HAS. The DNA binding subunit MSL2 alone can enrich X chromosomal MREs in vitro, although MSL2 misses most MREs within HAS (Villa et al., 2016). The Chromatin Linked Adaptor for MSL Proteins (CLAMP) binds thousands of MREs genome wide and contributes to DCC targeting to HAS (Kaye et al., 2018; Soruco et al., 2013). The role of CLAMP in facilitating MSL2 targeting to HAS was investigated by several approaches. Monitoring MSL2 chromatin binding in vivo by chromatin immunoprecipitation with high throughput sequencing (ChIP seq) showed the requirement of CLAMP for HAS targeting. Next, the interplay between CLAMP and MSL2 in genome wide in vitro DNA binding was studied by DNA immunoprecipitation with high throughput sequencing (DIP seq) (Gossett and Lieb, 2008; Liu et al., 2005; Villa et al., 2016). The data revealed mutual recruitment of both factors to each other’s binding sites and cooperative binding to novel sites. This DNA binding cooperativity extended each other’s binding repertoire to facilitate robust binding of MREs located within HAS, although increased binding to other non functional sites was observed. Both factors interacted directly with each other in co IP experiments, providing an explanation for cooperative DNA binding. Whether CLAMP and MSL2 are required for keeping HAS nucleosome free was studied by assay for transposase accessibly chromatin with high throughput sequencing (ATAC seq) (Buenrostro et al., 2013; Buenrostro et al., 2015). Both factors cooperate to stabilize each other’s binding and to compete with nucleosome positioning at HAS. After successful binding of the DCC to HAS, it interacts with neighboring target genes, which are marked by trimethylation of histone H3K36 (H3K36me3). There, the DCC catalyzes acetylation of H4K16 (H4K16ac) to boost transcription (Akhtar and Becker, 2000; Gelbart et al., 2009; Larschan et al., 2007; Prestel et al., 2010). The DCC employs the chromosome 3D organization, which seems to be invariant between males and females, to transfer from HAS to active genes (Ramirez et al., 2015; Ulianov et al., 2016). The contribution of HAS to the chromosome interaction network was studied by using different chromosome conformation capture techniques. Hi C analysis on sex sorted embryos showed that, H4K16ac and H3K36me3 correlate well with the active compartments (Sexton et al., 2012). Interestingly, compartment switching on the X chromosome between males and females was correlated with H4K16ac and therefore attributed to dosage compensation. The involvement of the Pioneering sites on the X (PionX), a special sub-class of HAS, in chromosome architecture was studied by high resolution 4C seq in male and female cells. Chromosomal segments containing PionX made frequent contact with many loci within the active compartment and even looped over large domains of the inactive compartment (Ghavi-Helm et al., 2014). These long range interactions between PionX with other PionX/HAS were more robust in males compared to females, indicating that the dosage compensation machinery reinforced them. Moreover, de novo induction of DCC assembly in female cells showed that the DCC uses long range interaction within the active compartment to transfer from PionX to target genes marked by H3K36me3 for up regulation of transcription. The chromosomal kinase JIL 1, which catalyzes phosphorylation of histone H3S10, localizes also to actively transcribed genes marked by H3K36me3 and is two fold enriched on the male X chromosome (Jin et al., 2000; Regnard et al., 2011; Wang et al., 2001). JIL 1 is implicated in maintaining overall chromosome organization and preventing the spreading of heterochromatin into the euchromatic part of the X chromosome in both sexes (Cai et al., 2014; Ebert et al., 2004; Jin et al., 1999). Furthermore, JIL 1 localizes to the non LTR retrotransposon arrays of the telomeres to positively regulate their expression (Andreyeva et al., 2005; Silva-Sousa and Casacuberta, 2013; Silva-Sousa et al., 2012). The role of JIL 1 in regulating gene expression was studied using various methods. JIL 1 formed a stable complex with the novel PWWP domain containing protein, JIL 1 Anchoring and Stabilizing Protein (JASPer). The JIL 1 JASPer (JJ) complex specifically enriched H3K36me3 modified nucleosomes in vitro via JASPer’s PWWP domain from a nucleosome library containing 115 different nucleosome types. Consistently, ChIP seq experiments showed that the JJ complex localizes to H3K36me3 chromatin at active gene bodies and at telomeric transposons in vivo. As previously described, the JJ complex is also enriched on the male X chromosome relative to autosomes. Loss of JIL 1 resulted in loss of JASPer enrichment, a small increase in H3K9me2 and a decrease in H4K16ac on the X chromosome shown by spike in ChIP seq. Gene expression analysis by RNA seq showed that the JJ complex positively regulates expression of genes, in particular of genes from the male X chromosome, and of telomeric transposons. Furthermore, the JJ complex associated with the Set1/COMPASS complex and with other remodelling complexes as shown by co IP coupled to mass spectrometry analysis.

Pore-ing the right dose.

Abstract: Dosage compensation in Drosophila melanogaster is distinguished by the hypertranscription of the male X chromosome. New findings show that this process requires the nuclear pore complex.