The XXXX substitution in A-type lamins deregulates @entity21434 activity in Dunnigan-type familial partial lipodystrophy.

@entity1 @entity4223 @entity18417 @entity66652 @entity21434
UNASSIGNED: Nuclear lamins are involved in many cellular functions due to their ability to bind numerous partners including chromatin and transcription factors, and affect their properties. @entity18417 ( @entity4223 ; OMIM#151660) is caused in most cases by the A-type lamin @entity66652 mutation. We report here that the @entity66652 mutation affects the regulatory activity of @entity21434 , a transcription factor that regulates hundreds of genes involved in lipid metabolism and adipocyte differentiation. Using in situ proximity ligation assays, reporter assays and biochemical and transcriptomic approaches, we show that interactions of @entity21434 with @entity4223 ( @entity4223 ) and @entity4223 ( @entity4223 ) occur at the nuclear periphery and in the nucleoplasm. These interactions involve the Ig-fold of A-type lamins and are favored upon @entity21434 binding to its DNA target sequences. We show that @entity21434 , @entity4223 and sterol response DNA elements form ternary complexes in vitro. In addition, overexpression of A-type lamins reduces transcriptional activity of @entity21434 . In contrast, both overexpression of @entity4223 @entity66652 in primary @entity1 preadipocytes and endogenous expression of A-type lamins @entity66652 in @entity4223 @entity1 fibroblasts, reduce A-type lamins- @entity21434 in situ interactions and upregulates a large number of @entity21434 target genes. As this @entity4223 mutant was previously shown to inhibit adipogenic differentiation, we propose that deregulation of @entity21434 by mutated A-type lamins constitutes one underlying mechanism of the physiopathology of @entity4223 . Our data suggest that @entity21434 targeting molecules could be considered in a therapeutic context.
