Distinct and shared transcriptomes are regulated by microphthalmia-associated transcription factor isoforms in mast cells.
The Microphthalmia-associated transcription factor (Mitf) is an essential basic helix-loop-helix leucine zipper transcription factor for mast cell development. Mice deficient in Mitf harbor a severe mast cell deficiency, and Mitf-mutant mast cells cultured ex vivo display a number of functional defects. Therefore, an understanding of the genetic program regulated by Mitf may provide important insights into mast cell differentiation. Multiple, distinct isoforms of Mitf have been identified in a variety of cell types; we found that Mitf-a, Mitf-e, and Mitf-mc were the major isoforms expressed in mast cells. To determine the physiologic function of Mitf in mast cells, we restored expression of these isoforms in primary mast cells from Mitf(-/-) mice. We found that these isoforms restored granular morphology and integrin-mediated migration. By microarray analysis, proteases, signaling molecules, cell surface receptor, and transporters comprised the largest groups of genes up-regulated by all isoforms. Furthermore, we found that isoforms also regulated distinct genes sets, suggesting separable biological activities. This work defines the transcriptome regulated by Mitf in mast cells and supports its role as master regulator of mast cell differentiation. Expression of multiple isoforms of this transcription factor may provide for redundancy of biological activities while also allowing diversity of function.
Shahlaee
Amir H
AH
Division of Pediatric Hematology, Johns Hopkins University, Baltimore, MD 21205, USA. ctakemot@jhmi.edu
Brandal
Stephanie
S
Lee
Youl-Nam
YN
Jie
Chunfa
C
Takemoto
Clifford M
CM
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D016023:Integrins / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic
D016023:Integrins; D051739:Microphthalmia-Associated Transcription Factor; D020033:Protein Isoforms