Combinatorial effects of splice variants modulate function of Aiolos.
The transcription factor Aiolos (also known as IKZF3), a member of the Ikaros family of zinc-finger proteins, plays an important role in the control of B lymphocyte differentiation and proliferation. Previously, multiple isoforms of Ikaros family members arising from differential splicing have been described and we now report a number of novel isoforms of Aiolos. It has been demonstrated that full-length Ikaros family isoforms localize to heterochromatin and that they can associate with complexes containing histone deacetylase (HDAC). In this study, for the first time we directly investigate the cellular localization of various Aiolos isoforms, their ability to heterodimerize with Ikaros and associate with HDAC-containing complexes, and the effects on histone modification and binding to putative targets. Our work demonstrates that the cellular activities of Aiolos isoforms are dependent on combinations of various functional domains arising from the differential splicing of mRNA transcripts. These data support the general principle that the function of an individual protein is modulated through alternative splicing, and highlight a number of potential implications for Aiolos in normal and aberrant lymphocyte function.
Caballero
Rosalia
R
Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Setien
Fernando
F
Lopez-Serra
Lidia
L
Boix-Chornet
Manuel
M
Fraga
Mario F
MF
Ropero
Santiago
S
Megias
Diego
D
Alaminos
Miguel
M
Sanchez-Tapia
Eva M
EM
Montoya
Maria C
MC
Esteller
Manel
M
Gonzalez-Sarmiento
Rogelio
R
Ballestar
Esteban
E
D017398:Alternative Splicing; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D019281:Dimerization; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
D006657:Histones; C106285:IKZF3 protein, human; D020033:Protein Isoforms; D014157:Transcription Factors; D051740:Ikaros Transcription Factor; D006655:Histone Deacetylases