Biology subjects

Megeney, L. A.

Publications and source records attributed to Megeney, L. A..

3 recordsLinked to original sources

bioRxiv2024

Caspase-Activated DNase Localizes to Cancer Causing Translocation Breakpoints During Cell Differentiation

Caspase activated DNase (CAD) induced DNA breaks promote cell differentiation and therapy-induced cancer cell resistance. CAD targeting activity is assumed to be unique to each condition, as differentiation and cancer genesis are divergent cell fates. Here, we made the surprising discovery that a subset of CAD-bound targets in differentiating muscle cells are the same genes involved in the genesis of cancer-causing translocations. In muscle cells, a prominent CAD-bound gene pair is Pax7 and Foxo1a, the mismatched reciprocal loci that give rise to alveolar rhabdomyosarcoma. We show that CAD-targeted breaks in the Pax7 gene are physiologic to reduce Pax7 expression, a prerequisite for muscle cell differentiation. A cohort of these CAD gene targets are also conserved in early differentiating T cells and include genes that spur leukemia/lymphoma translocations. Our results suggest the CAD targeting of translocation prone oncogenic genes is non-pathologic biology and aligns with initiation of cell fate transitions.

genomics↗

bioRxiv2024

SMCHD1 activates the expression of genes required for the expansion of human myoblasts

SMCHD1 is an epigenetic regulatory protein known to modulate the targeted repression of large chromatin domains. Diminished SMCHD1 function in muscle fibers causes Facioscapulohumeral Muscular Dystrophy (FSHD2) through derepression of the D4Z4 chromatin domain, an event which permits the aberrant expression of the disease-causing gene DUX4. Given that SMCHD1 plays a broader role in establishing the cellular epigenome, we examined whether loss of SMCHD1 function might affect muscle homeostasis through additional mechanisms. Here we show that acute depletion of SMCHD1 results in a DUX4-independent defect in myoblast proliferation. Genomic and transcriptomic experiments determined that SMCHD1 associates with enhancers of genes controlling cell cycle to activate their expression. Amongst these cell cycle regulatory genes, we identified LAP2 as a key target of SMCHD1 required for the expansion of myoblasts, where the ectopic expression of LAP2 rescues the proliferation defect of SMCHD1-depleted cells. Thus, the epigenetic regulator SMCHD1 can play the role of a transcriptional co-activator for maintaining the expression of genes required for muscle progenitor expansion. This DUX4-independent role for SMCHD1 in myoblasts suggests that the pathology of FSHD2 may be a consequence of defective muscle regeneration in addition to the muscle wasting caused by spurious DUX4 expression. Chromatin modifier SMCHD1 regulates the proliferation of human myoblasts SMCHD1 binds to enhancers of cell cycle regulatory genes to activate their expression Lap2 is an SMCHD1 direct target gene that regulates the expansion of human myoblasts.

cell biology↗

bioRxiv2019

Chromatin reorganization during myoblast differentiation involves the caspase-dependent removal of SATB2

Induction of lineage-specific gene programs are strongly influenced by alterations in local chromatin architecture. However, key players that impact this genome reorganization remain largely unknown. Here, we report that removal of special AT-rich binding protein 2 (SATB2), a nuclear protein that binds matrix attachment regions, is a key event in initiating myogenic differentiation. Deletion of SATB2 in muscle cell culture models and in vivo, accelerates differentiation and depletes the muscle progenitor pool, respectively. Genome wide analysis indicates that SATB2 binding is both repressive and inductive, as loss of SATB2 leads to expression of differentiation regulatory factors and inhibition of genes that impair this process. Finally, we noted that the differentiation-specific decline in SATB2 protein is dependent on a caspase 7-mediated cleavage event. Taken together, this study demonstrates that temporal control of SATB2 protein is critical for shaping the chromatin environment and coordinating the myogenic differentiation program. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/883579v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@12ca82corg.highwire.dtl.DTLVardef@d50a56org.highwire.dtl.DTLVardef@99ba7borg.highwire.dtl.DTLVardef@a216e3_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

molecular biology↗