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The Role of MITF in Regulating Human Pigmentation

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The Role of MITF in Regulating Human Pigmentation The role of MITF in regulating human pigmentation Christian Praetorius Thesis for the degree of Philosophiae Doctor August 2014 UNIVERSITY OF ICELAND SCHOOL OF HEALTH SCIENCES FACULTY OF MEDICINE Hlutverk MITF við stjórnun húðlitar í mönnum Christian Praetorius Ritgerð til doktorsgráðu Umsjónarkennari Eiríkur Steingrímsson Doktorsnefnd Ólafur S. Andrésson Zophonías O. Jónsson Magnús Karl Magnússon Hendrik G. Stunnenberg August 2014 UNIVERSITY OF ICELAND SCHOOL OF HEALTH SCIENCES FACULTY OF MEDICINE The role of MITF in regulating human pigmentation Christian Praetorius Thesis for the degree of Philosophiae Doctor Supervisor Eiríkur Steingrímsson Doctoral Comittee Ólafur S. Andrésson Zophonías O. Jónsson Magnús Karl Magnússon Hendrik G. Stunnenberg August 2014 UNIVERSITY OF ICELAND SCHOOL OF HEALTH SCIENCES FACULTY OF MEDICINE Thesis for a doctoral degree at the University of Iceland. All right reserved. No part of this publication may be reproduced in any form without the prior permission of the copyright holder. © Christian Praetorius 2014 Document typeset with LATEX. ISBN: 978-9935-9200-2-7 Printing by Háskolaprent Reykjavík, Iceland 2014 Ágrip Þroskun litfruma og myndun sortuæxla er háð umritunarþættinum microphthal- mia associated transcription factor (MITF) en hann tilheyrir basic-helix-loop-helix leucine zipper (bHLH-LZ) fjölskyldunni. MITF stjórnar tjáningu fjölda gena í litfrumum og sortuæxlum, þar með talið gena sem eru mikilvæg fyrir framleiðslu litarefnisins melanin, og gena sem stjórna frumuhringnum, frumufari og lifun. Þessi þekktu markgen skýra þó ekki að fullu hlutverk MITF í litfrumum og sortuæxlum. Við notuðum tvískipta tjáningarrannsókn til að finna markgen MITF í sor- tuæxlum. Í fyrsta lagi leituðum við að genum sem fylgja tjáningarmynstri MITF gensins sortuæxlissýnum. Í öðru lagi skoðuðum við hvaða gen eru tjáð þegar MITF er yfirtjáð í sortuæxlisfrumulínunni Skmel28. Af þeim genum sem voru á báðum listunum var fjöldi þekktra markgena MITF en einnig nokkur gen sem ekki hefur verið sýnt að stjórnist af MITF svo sem umritunarþættirnir IRF4 og TFAP2alpha. Hlutverk þeirra var skoðað frekar. Erfðamengisrannsóknir hafa sýnt að breytileiki í IRF4 geninu í mönnum tengist freknum, ljósri húð, brúnu hári og bláum augum. IRF4 genið gegnir mikilvægu hlutverki í ónæmiskerfinu og hefur verið kallað "lineage survival oncogene" í mergfrumuæxlum. Ekki hefur áður verið sýnt hvaða hlutverki það gegnir í litfrumum. Hér sýnum við að tjáning IRF4 gensins er háð MITF. Tjáning Irf4 gensins er næstum engin í Mitf stökkbreyttum músum eða þegar MITF genið er slegið út í sortuæxlisfrumum í rækt með notkun shRNA. MITF stjórnar tjáningu IRF4 gensins með því að bindast stjórnröðum í innröð 4 í IRF4, og er þessi örvun umritunar einnig háð umritunarþættinum TFAP2A. Breytileikinn sem tengist litareinkennum í mönnum (rs12203592-T) skarast við bindiset TFAP2A próteinsins og þegar upprunalega C-basanum er breytt í T getur TFAP2A ekki bundist lengur og tjáning IRF4 minnkar, bæði í in vitro tilraunum og í litfrumum úr einstaklingum sem eru arfhreinir fyrir T samsætuna. Tilraunir sýna að MITF og IRF4 vinna saman að því að virkja tjáningu litargensins TYR og að þegar IRF4 bindisetum í stjórnröð MITF er stökkbreytt getur þessi samvinna ekki átt sér stað lengur. Rannsókn þessi sýnir því bein tengsl milli breytileika í innröð IRF4 gensins og áhrifa á tjáningu ensíms sem ákvarðar litarhátt manna. Lykilorð: MITF, IRF4, genatjáning, litarháttur, freknur Abstract The development of melanocytes and melanoma depends on the presence of the microphthalmia-associated transcription factor (MITF), a member of the basic helix-loop-helix-leucine zipper (bHLH-LZ) transcription factor family. MITF has been shown to regulate a broad range of genes, ranging from genes important for pigment production, to genes involved in cell cycle regulation, migration and survival. Nevertheless, the known MITF target genes do not explain all the roles of MITF in melanocyte development and melanoma progression. We have used a novel microarray approach to characterize MITF target genes in melanomas. First we identified genes which correlate with the expression of MITF in human melanoma samples. Second, we compared the genes expressed in a stably MITF-transfected line of SKmel28 cells with the genes expressed in SKmel28 cells without MITF. Third, we compared the two lists of genes to obtain a list of genes potentially regulated by MITF. A number of the genes thus identified are known MITF target genes, whereas the rest represent novel targets. Among the novel targets are two transcription factors, IRF4 and TFAP2a which were analyzed further. Genome-wide association studies have shown that a polymorphism in the human IRF4 gene is associated with fair skin and light/blue eye color, suggesting that the gene plays an important role in melanocytes. IRF4 has been shown to play a key role in lymphoid, myeloid and dendritic cell differentiation and to act as a lineage survival oncogene in multiple myeloma. However, its role in melanocytes has not been characterized. Here we show that expression of the IRF4 gene is dramatically reduced in Mitf mutant mice and upon MITF knockdown using shRNA. MITF activates IRF4 expression by binding regulatory sequences in intron 4 of the IRF4 gene and depends on another transcription factor, TFAP2a for this activation. The binding site for TFAP2a is located at the same position as the rs12203592 polymorphism and when changed from C to T (as in rs12203592), TFAP2a can not bind and IRF4 expression is reduced in both reporter assays and in melanocytes from individuals homozygous for the T allele. Importantly, IRF4 and MITF cooperatively activate the expression of the pigmentation gene TYR; mutating the IRF4 binding sites in TYR eliminates this cooperative effect. Thus, a direct link has been provided where a functional polymorphism in the IRF4 gene leads to reduced expression of a target gene encoding an enzyme essential for pigmentation. Keywords: MITF, IRF4, gene expression, pigmentation, freckles Acknowledgements The research for this thesis was carried out at the Department of Biochemistry and Molecular Biology at the Faculty of Medicine of the University of Iceland. Many people have supported me directly or indirectly and I would like to thank all of them for their kindness and support. First of all I would like to thank my supervisor Professor Eiríkur Steingrímsson for the possibility to work in his laboratory, his scientific guidance, critical and lively discussion and for the support throughout all these years, it was a great time. I also like to thank all colleagues from the Steingrímsson Lab for their help, support and also for the critical discussions of results in the lab meetings: Kristín Bergsteindóttir, Christine Grill, Benedikta S. Hafliðadóttir, Erna Magnúsdóttir, Margrét H. Ögmundsdóttir and Alexander Schepsky. I wish to acknowledge the help and support from the other colleagues from the 5th floor at Læknagarður: Jónína Jóhannsdóttir, Sif Jónsdóttir, Guðrun Valdimarsdóttir, Pétur Henry Petersen, Stefán Þ. Sigurðsson and Hans Guttormor Þormar. I would like to thank my PhD committee, Prof. Ólafur S. Andrésson, Prof. Zophonías O. Jónsson, Prof. Magnús Karl Magnússon and Prof. Hendrik G. Stunnenberg for their opinions on my thesis. I also thank the evaluating commit- tee Prof. Helga Ögmundsdóttir, Prof. Zophonías O. Jónsson and Prof. Robert Kelsh for their work. Finally I would like to thank my family, Maren, Sophie and Lisa for their patience and support, without them it would have never been possible to finish this thesis. This work was supported by grants from the Icelandic Research Fund, the University of Iceland Research Fund and the Eimskip University Fund for doctoral studies. Contents Ágrip .................................. VII Abstract ................................IX Acknowledgements ..........................XI Contents ................................ XIII List of Abbreviations ......................... XVI List of Figures ............................. XIX List of Tables ..............................XX List of Original Publications ..................... XXI Declaration of contribution ...................... XXII 1. Introduction ............................1 1.1. Pigmentation ..........................1 1.1.1. Melanocytes ......................1 1.1.2. Melanosome biology ..................2 1.1.3. Melanocytes in the hair follicle .............4 1.1.4. Synthesis of pigment ..................5 1.2. The microphthalmia associated transcription factor ......6 1.3. Mutations in the MITF gene ..................6 1.4. Mitf protein structure ......................7 1.5. MITF gene structure and splice variants ............9 1.6. Regulation of MITF expression .................9 1.6.1. Sry-related HMG box 10 (SOX10) ...........9 1.6.2. Paired box 3 transcription factor (PAX3) ....... 10 1.6.3. Signal transducer and activator of transcription 3 (STAT3) ........................ 11 1.6.4. Protein inhibitor of activated STAT3 (PIAS3) ..... 11 1.6.5. cAMP response element binding protein (CREB) ... 11 1.6.6. Lymphoid-enhancing factor-1 (LEF-1) ......... 11 1.6.7. BRN2 .......................... 11 XIV Contents 1.6.8. Forkhead-box transcription factor D3 (FOXD3) .... 12 1.6.9. Tyro3 .......................... 12 1.6.10. micro RNA ....................... 12 1.7. Post-translational modifications of MITF ........... 13 1.7.1. Phosphorylation of MITF ................ 13 1.7.2. Acetylation of MITF .................. 14 1.7.3. Ubiquitination of MITF ................
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