title: A filtering strategy identifies FOXQ1 as a potential effector of lamin A dysfunction.
abstract: Small increases in the expression of wild-type prelamin A are sufficient to recapitulate the reduced cell proliferation and altered nuclear membrane morphology observed in cells expressing progerin, the mutant lamin A associated with progeria. We hypothesized that the manifestation of these phenotypes in cells expressing elevated levels of wild-type prelamin A or progerin is caused by the same molecular effectors, which play a central role in the onset of the progeroid phenotype. To experimentally test this hypothesis, we compared the transcriptomes of isogenic diploid fibroblasts expressing progerin or elevated levels of wild-type prelamin A with that of wild-type fibroblasts. We subsequently used the reversion towards normal of two phenotypes, reduced cell growth and dismorphic nuclei, by treatment with farnesyltransferase inhibitor (FTI) or overexpression of ZMPSTE24, as a filtering strategy to identify genes linked to the onset of these two phenotypes. Through this analysis we identified the gene encoding for the transcription factor FOXQ1, as a gene whose expression is induced in both cells expressing progerin and elevated levels of wild-type prelamin A, and subsequently reduced in both cell types upon conditions that ameliorate the phenotypes. We overexpressed FOXQ1 in normal fibroblasts and demonstrated that increased levels of this factor lead to the development of both features that were used in the filtering strategy. These findings suggest a potential link between this transcription factor and cell dysfunction induced by altered prelamin A metabolism.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Candelario
authors.forename: Leng-Ying
authors.initials: LY
authors.lastname: Chen
authors.forename: Paul
authors.initials: P
authors.lastname: Marjoram
authors.forename: Sita
authors.initials: S
authors.lastname: Reddy
authors.forename: Lucio
authors.initials: L
authors.lastname: Comai
mesh_terms: D002460:Cell Line; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D034904:Lamin Type A; D008565:Membrane Proteins / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011371:Progeria / Q000235:genetics* / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051858:Forkhead Transcription Factors; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D051231:Farnesyltranstransferase; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human