Identification of Chromatin Modifier Genes Important for DUX4 Silencing

Investigators: Daniel G Miller MD PhD, Galina N Filippova PhD

Category: Research - Basic

Friends of FSH Research and FSHD Canada Foundation are pleased to support the Daniel G. Miller MD PhD & Galina Filippova PhD project entitled "Identification of Chromatin Modifier Genes Important for DUX4 Silencing."

Facioscapulohumeral Muscular Dystrophy is a dominantly inherited myopathy associated with chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4. DUX4 is encoded within each unit of the D4Z4 array where it is normally transcriptionally silenced and packaged as constitutive heterochromatin. Truncation of the array to less than 11 D4Z4 units (FSHD1) or mutations in SMCHD1 (FSHD2) results in chromatin relaxation and a small percentage of cultured myoblasts from these individuals exhibit infrequent bursts of DUX4 expression. This proposal builds on the hypothesis that epigenetic modification of D4Z4 chromatin structure is an important strategy for disease treatment. Here we propose to construct a library of siRNA’s that target genes involved in chromatin modification and examine the effect of reducing transcript levels on DUX4 gene expression to determine integral components of the DUX4 transcriptional silencing machinery.

This grant was also supplemented with a capacity-building grant to hire techincal staff for the Miller Lab:

Screening Chromatin Modifying Genes

Ira Martopullo

Budget

$42,160 for 1 year

Lay Abstract

Ira comes to the Miller Lab from the Kyba Lab at the University of Minnesota, where she most recently participated in a research project focused on understanding the molecular regulation of differentiation and self-renewal of skeletal muscle cells.

At the Miller Lab Ira will provide technical support for screening chromatin modifying genes that may affect DUX4 regulation. She will be constructing the siRNA library, preparing and characterizing cells for the screening platform, and overseeing the screening process. Once "hits" are identified she will evaluate gene targets identified in the screen to confirm their involvement in DUX4 transcriptional silencing and determine if multiple hits are part of common pathways.

Related Material

See Article Research Publication: Catching DUX4 red (or green)-handed

See resulting publication Endogenous DUX4 Expression in FSHD Myotubes is Sufficient to Cause Cell Death and Disrupts RNA Splicing and Cell Migration Pathways