Flightless-I governs cell fate by recruiting the SUMO isopeptidase SENP3 to distinctHOXgenes.
Despite recent studies on the role of ubiquitin-related SUMO modifier in cell fate decisions, our understanding on precise molecular mechanisms of these processes is limited. Previously, we established that the SUMO isopeptidase SENP3 regulates chromatin assembly of the MLL1/2 histone methyltransferase complex at distinctHOXgenes, including the osteogenic master regulatorDLX3. A comprehensive mechanism that regulates SENP3 transcriptional function was not understood.



Here, we identified flightless-I homolog (FLII), a member of the gelsolin family of actin-remodeling proteins, as a novel regulator of SENP3. We demonstrate that FLII is associated with SENP3 and the MLL1/2 complex. We further show that FLII determines SENP3 recruitment and MLL1/2 complex assembly on theDLX3gene. Consequently, FLII is indispensible for H3K4 methylation and proper loading of active RNA polymerase II at this gene locus. Most importantly, FLII-mediated SENP3 regulation governs osteogenic differentiation of human mesenchymal stem cells.



Altogether, these data reveal a crucial functional interconnection of FLII with the sumoylation machinery that converges on epigenetic regulation and cell fate determination.
Institute of Biochemistry II, Goethe University Medical School, University Hospital Building 75, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Arnab
A
Nayak
Department of Oral and Maxillofacial Surgery, University of Regensburg, 93042 Regensburg, Germany.
Anja
A
Reck
Department of Oral and Maxillofacial Surgery, University of Regensburg, 93042 Regensburg, Germany.
Christian
C
Morsczeck
Institute of Biochemistry II, Goethe University Medical School, University Hospital Building 75, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Stefan
0000-0002-8792-7700
S
Müller
D002454:Cell Differentiation; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003795:Dental Sac / Q000166:cytology; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007553:Isotope Labeling; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D058207:Sumoylation; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C088334:Distal-less homeobox proteins; C098179:FLII protein, human; D006657:Histones; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C525671:MEOX1 protein, human; D008840:Microfilament Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; D003546:Cysteine Endopeptidases; C499718:SENP3 protein, human
Chromatin; Flightless-I; HOX gene; MLL1/2; Mesenchymal stem cells; SILAC-based proteomics; Sumoylation