DUX4-Induced Histone Variants H3.X and H3.Y Mark DUX4 Target Genes for Expression

Resnick, Rebecca; Wong, Chao-Jen; Hamm, Danielle C.; Bennett, Sean; Skene, Peter J.; Hake, Sandra B.; Henikoff, Steven; Maarel, Silvère M. van der; Tapscott, Stephen J.

doi:10.1016/j.celrep.2019.10.025

Cited by 39 publications

(56 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Small populations of DUX4-positive myotubes are thought to drive pathogenesis in FSHD [2][3][4]. We found 0.1% (16/15,687) of nuclei expressed DUX4 using single-nucleus RNA-seq which is lower than the reported 0.5% (1/200 in myotube nuclei) [8,10,16,27] possibly due to variability in expression levels of DUX4 between individuals. However, the percentage of DUX4-affected nuclei we found (3.7%, 583/15,687) is higher than that reported in FSHD single myocytes (0.55%, 27/4902) [29].…”

Section: Discussioncontrasting

confidence: 69%

“…Altered myogenesis in FSHD cells has been shown in previous studies [26]. Recently, a study showed upregulation and incorporation of alternate histones H3.X and H3.Y following DUX4 expression [27]. In this study, H3.Y (AKA RP11-432M8.17) has increased expression in FSHD2 cells and is included in our FSHD-induced genes.…”

supporting

confidence: 69%

“…Previous studies suggested a feedback loop between DUX4 and its target genes to further increase DUX4 expression via (1) DUX4-mediated proteolytic degradation of UPF1 and inhibition of nonsense-mediated RNA decay resulting in stabilization of DUX4 mRNA [37], and (2) the DUX4 target MBD3Ls binding to D4Z4 and relieving DUX4 repression [34]. Additionally, alternate histones which are targets of DUX4 have been shown to continue the expression of DUX4 target genes [27]. In the current study, we provide support for DUXA as another regulator of DUX4 target genes which may amplify the DUX4 gene network.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, our approach enables us to uniquely address how DUX4 expression, even in a single nucleus, results in target gene activation in other nuclei in the same myotube (due to the DUX4 protein spreading) under native condition to distinguish the FSHD-Hi and FSHD-Lo population of cells. We analyzed the expression of 67 DUX4 target genes used in Heuvel, et al [20,27] in our FSHD-Hi and FSHD-Lo myotube single nucleus populations. For the Smart-Seq nuclei, all FSHD-Hi nuclei and about 3.3% of FSHD-Lo nuclei highly express at least 5 of these genes (S14 Fig).…”

Section: Day 3 Fshd2 Myotube Nuclei Expression Patterns Are Similar Amentioning

confidence: 99%

See 3 more Smart Citations

Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei

et al. 2020

View full text Add to dashboard Cite

FSHD is characterized by the misexpression of DUX4 in skeletal muscle. Although DUX4 upregulation is thought to be the pathogenic cause of FSHD, DUX4 is lowly expressed in patient samples, and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile of DUX4 and its targets, we performed bulk RNA-seq on a 6-day differentiation time-course in primary FSHD2 patient myoblasts. We identify a set of 54 genes upregulated in FSHD2 cells, termed FSHD-induced genes. Using single-cell and single-nucleus RNA-seq on myoblasts and differentiated myotubes, respectively, we captured, for the first time, DUX4 expressed at the single-nucleus level in a native state. We identified two populations of FSHD myotube nuclei based on low or high enrichment of DUX4 and FSHD-induced genes ("FSHD-Lo" and "FSHD Hi", respectively). FSHD-Hi myotube nuclei coexpress multiple DUX4 target genes including DUXA, LEUTX and ZSCAN4, and also upregulate cell cycle-related genes with significant enrichment of E2F target genes and p53 signaling activation. We found more FSHD-Hi nuclei than DUX4-positive nuclei, and confirmed with in situ RNA/protein detection that DUX4 transcribed in only one or two nuclei is sufficient for DUX4 protein to activate target genes across multiple nuclei within the same myotube. DUXA (the DUX4 paralog) is more widely expressed than DUX4, and depletion of DUXA suppressed the expression of LEUTX and ZSCAN4 in late, but not early, differentiation. The results suggest that the DUXA can take over the role of DUX4 to maintain target gene expression. These results provide a possible explanation as to why it is easier to detect DUX4 target genes than DUX4 itself in patient cells and raise the possibility of a self-sustaining network of gene dysregulation triggered by the limited DUX4 expression.

show abstract

Section: Discussioncontrasting

confidence: 69%

supporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Day 3 Fshd2 Myotube Nuclei Expression Patterns Are Similar Amentioning

confidence: 99%

See 2 more Smart Citations

Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A recent study by Resnick et al (2019) further showed that DUX4 induces H3.X and H3.Y expression, as well as causes the increased incorporation of these histone variants into the nucleosomes of its target genes [102]. H3.X and H3.Y are associated with relaxed chromatin regions and have been found to greatly facilitate DUX4 target gene-specific induction and perdurance.…”

Section: Gene Regulationmentioning

confidence: 98%

DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy

Lim

Nguyen

Yokota

2020

IJMS

View full text Add to dashboard Cite

Facioscapulohumeral muscular dystrophy (FSHD) is a disabling inherited muscular disorder characterized by asymmetric, progressive muscle weakness and degeneration. Patients display widely variable disease onset and severity, and sometimes present with extra-muscular symptoms. There is a consensus that FSHD is caused by the aberrant production of the double homeobox protein 4 (DUX4) transcription factor in skeletal muscle. DUX4 is normally expressed during early embryonic development, and is then effectively silenced in all tissues except the testis and thymus. Its reactivation in skeletal muscle disrupts numerous signalling pathways that mostly converge on cell death. Here, we review studies on DUX4-affected pathways in skeletal muscle and provide insights into how understanding these could help explain the unique pathogenesis of FSHD.

show abstract

Casting histone variants during mammalian reproduction

Karam

Molaro

2023

Chromosoma

View full text Add to dashboard Cite

During mammalian reproduction, germ cell chromatin packaging is key to prepare parental genomes for fertilization and to initiate embryonic development. While chromatin modifications such as DNA methylation and histone post-translational modifications are well known to carry regulatory information, histone variants have received less attention in this context. Histone variants alter the stability, structure and function of nucleosomes and, as such, contribute to chromatin organization in germ cells. Here, we review histone variants expression dynamics during the production of male and female germ cells, and what is currently known about their parent-of-origin effects during reproduction. Finally, we discuss the apparent conundrum behind these important functions and their recent evolutionary diversification.

show abstract

DUX4-Induced Histone Variants H3.X and H3.Y Mark DUX4 Target Genes for Expression

Cited by 39 publications

References 40 publications

Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei

Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei

DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy

Casting histone variants during mammalian reproduction

Contact Info

Product

Resources

About