DUX4-induced HSATII RNA accumulation drives protein aggregation impacting RNA processing pathways.

Unlabelled: RNA-driven protein aggregation leads to cellular dysregulation by sequestering regulatory proteins, disrupting normal cellular processes, and contributing to the development of diseases and tumorigenesis. Here, we show that double homeobox 4 (DUX4), an early embryonic transcription factor and causative gene of facioscapulohumeral muscular dystrophy (FSHD), induces the accumulation of stable intranuclear RNAs, including nucleolar-associated RNA and human satellite II (HSATII) repeat RNA. Stable intranuclear RNAs drive protein aggregation in DUX4-expressing muscle cells.

Facioscapulohumeral Dystrophy: Molecular Basis and Therapeutic Opportunities.

Facioscapulohumeral dystrophy (FSHD) is caused by misexpression of the early embryonic transcription factor Double Homeobox Protein 4 (DUX4) in skeletal muscle. DUX4 is normally expressed at the 4-cell stage of the human embryo and initiates a portion of the first wave of embryonic gene expression that establishes the totipotent cells of the embryo. Following brief expression, the locus is suppressed by epigenetic silencing and remains silenced in nearly all somatic cells.

DUX4-induced HSATII transcription causes KDM2A/B-PRC1 nuclear foci and impairs DNA damage response.

Polycomb repressive complexes regulate developmental gene programs, promote DNA damage repair, and mediate pericentromeric satellite repeat repression. Expression of pericentromeric satellite repeats has been implicated in several cancers and diseases, including facioscapulohumeral dystrophy (FSHD). Here, we show that DUX4-mediated transcription of HSATII regions causes nuclear foci formation of KDM2A/B-PRC1 complexes, resulting in a global loss of PRC1-mediated monoubiquitination of histone H2A.

Chromodomain helicase DNA-binding 4 (CHD4) regulates early B cell identity and V(D)J recombination.

B lymphocytes develop from uncommitted precursors into immunoglobulin (antibody)-producing B cells, a major arm of adaptive immunity. Progression of early progenitors to antibody-expressing cells in the bone marrow is orchestrated by the temporal regulation of different gene programs at discrete developmental stages. A major question concerns how B cells control the accessibility of these genes to transcription factors.

Intermediate-term survival of robot-assisted versus open radical cystectomy for muscle-invasive and high-risk non-muscle invasive bladder cancer in The Netherlands.

Background: Radical cystectomy with pelvic lymph node dissection is the recommended treatment in non-metastatic muscle-invasive bladder cancer (MIBC). In randomised trials, robot-assisted radical cystectomy (RARC) showed non-inferior short-term oncological outcomes compared with open radical cystectomy (ORC). Data on intermediate and long-term oncological outcomes of RARC are limited.