Abstract
Muscle-enriched A-type lamin-interacting protein (Mlip) is a recently discovered Amniota gene that encodes proteins of unknown biological function. Here we report Mlip’s direct interaction with chromatin, and it may function as a transcriptional co-factor. Chromatin immunoprecipitations with microarray analysis demonstrated a propensity for Mlip to associate with genomic regions in close proximity to genes that control tissue-specific differentiation. Gel mobility shift assays confirmed that Mlip protein complexes with genomic DNA. Blocking Mlip expression in C2C12 myoblasts down-regulates myogenic regulatory factors (MyoD and MyoG) and subsequently significantly inhibits myogenic differentiation and the formation of myotubes. Collectively our data demonstrate that Mlip is required for C2C12 myoblast differentiation into myotubes. Mlip may exert this role as a transcriptional regulator of a myogenic program that is unique to amniotes.
Highlights
A-type lamins have been implicated in the maintenance of cellular commitment and differentiation
Muscle-enriched A-type lamin-interacting protein (Mlip) was shown to interact with Islet1 (Isl1), an essential transcription factor for cardiac progenitor cell specification [7,8], and blocks agonist-induced hypertrophy of cardiomyocytes in culture [9]; Mlip plays a critical role in the maintenance of cardiac homeostasis and protects the heart against pathophysiological stresses [10,11] and for normal myonuclear positioning in skeletal muscle [6,12]
Mlip localizes to micro-domains in the nucleus in close proximity to chromatin, in undifferentiated mouse C2C12 myoblasts (Figure 1A)
Summary
A-type lamins have been implicated in the maintenance of cellular commitment and differentiation. The recent discovery of a unique muscle-enriched A-type lamin-interacting protein (Mlip) [5] may provide valuable new insight into how primary genetic defects in LMNA, a ubiquitously expressed nuclear protein, translates to tissue-specific diseases. Mlip was shown to interact with Islet (Isl1), an essential transcription factor for cardiac progenitor cell specification [7,8], and blocks agonist-induced hypertrophy of cardiomyocytes in culture [9]; Mlip plays a critical role in the maintenance of cardiac homeostasis and protects the heart against pathophysiological stresses [10,11] and for normal myonuclear positioning in skeletal muscle [6,12].
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