Dynamic nature of active chromatin hubs

Aim. In order to get more information about organization of active chromatin hubs and their role in the regulation of gene transcription we have studied the spatial organization of the a-globin gene domain in cultured chicken erythroblasts. Methods. The chromosome conformation capture (3C) protocol...

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Datum:	2011
Hauptverfasser:	Gavrilov, A.A., Philonenko, E.S., Iarovaia, O.V., Razin, S.V.
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Sprache:	English
Veröffentlicht:	Інститут молекулярної біології і генетики НАН України 2011
Schriftenreihe:	Вiopolymers and Cell
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spelling	irk-123456789-1554402019-06-17T01:25:44Z Dynamic nature of active chromatin hubs Gavrilov, A.A. Philonenko, E.S. Iarovaia, O.V. Razin, S.V. Aim. In order to get more information about organization of active chromatin hubs and their role in the regulation of gene transcription we have studied the spatial organization of the a-globin gene domain in cultured chicken erythroblasts. Methods. The chromosome conformation capture (3C) protocol was employed to analyze the 3D configuration of the chicken a-globin gene domain. Results. We have demonstrated that in the same cell population the chicken domain of a-globin gene may be organized in two different active chromatin hubs. One of them appears essential for the activation of the a-globin gene expression while the other – for the activation of TMEM8 gene which constitutes a part of the a-globin gene domain in chicken, but not in human and other mammals. Importantly, two regulatory elements participate in the formation of both active chromatin hubs. Conclusions. The assembly of the same genomic area into two alternative chromatin hubs which share some regulatory elements suggests that active chromatin hubs are dynamic rather than static, and that regulatory elements may shuttle between different chromatin hubs. Keywords: active chromatin hub, globin gene, genomic domain, chromosome conformation capture. Мета. Щоб отримати нову інформацію стосовно організації активаторних хроматинових блоків та їхньої ролі в регуляції транскрипції ми вивчили просторову організацію домену a-глобінових генів у культивованих курячих еритробластах. Методи. Для анализу 3D конфігурації домену a-глобінових генів використано метод фіксації конформації хромосоми (3С). Результати. Ми продемонстрували, що в одній і тій самій популяції курячих клітин домен a-глобінових генів може бути організованим у два різних хроматинових блоки. Один з них необхідний для активації транскрипції a-глобінових генів, тоді як другий забезпечує активацію транскрипції гена TMEM8. Цей ген входить до складу домену aглобінових генів курей, але не ссавців і людини. Важливо, що два регуляторних елементи домену a-глобінових генів присутні у складі обох активаторних хроматинових блоків. Висновки. Існування в одному й тому ж геномному домені двох різних активаторних комплексів, які мають у своєму складі спільні регуляторні елементи, свідчить про динамічну природу активаторних хроматинових блоків, що дозволяє спільним регуляторним елементам періодично переміщуватися з одного комплексу в другий. Ключові слова: активаторні хроматинові блоки, глобіновий ген, геномний домен, метод фіксації хромосоми. Цель. Чтобы получить новую информацию об организации активаторных хроматиновых блоков и их роли в регуляции транскрипции, мы изучили пространственную организацию домена a-глобиновых генов в культивируемых куриных эритробластах. Методы. Для анализа 3D конфигурации домена a-глобиновых генов использован метод фиксации конформации хромосомы (3С). Результаты. Мы продемонстрировали, что в одной и той же популяции куриных клеток домен a-глобиновых генов может быть организован в два различных хроматиновых блока. Один из них необходим для активации транскрипции a-глобиновых генов, в то время как другой обеспечивает активацию транскрипции гена TMEM8. Этот ген входит в состав домена a-глобиновых генов кур, но не млекопитающих и человека. Важно, что два регуляторных элемента домена a-глобиновых генов присутствуют в составе обоих активаторных хроматиновых блоков. Выводы. Существование в одном и том же геномном домене двух разных активаторных комплексов, имеющих в своем составе общие регуляторные элементы, свидетельствует о динамической природе активаторных хроматиновых блоков, что позволяет общим регуляторным элементам периодически перемещаться из одного комплекса в другой. Ключевые слова: активаторные хроматиновые блоки, глобиновый ген, геномный домен, метод фиксации хромосомы. 2011 Article Dynamic nature of active chromatin hubs / A.A. Gavrilov, E.S. Philonenko, O.V. Iarovaia, S.V. Razin // Вiopolymers and Cell. — 2011. — Т. 27, № 5. — С. 364-368. — Бібліогр.: 17 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000124 http://dspace.nbuv.gov.ua/handle/123456789/155440 577.21 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України
institution	Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection	DSpace DC
language	English
description	Aim. In order to get more information about organization of active chromatin hubs and their role in the regulation of gene transcription we have studied the spatial organization of the a-globin gene domain in cultured chicken erythroblasts. Methods. The chromosome conformation capture (3C) protocol was employed to analyze the 3D configuration of the chicken a-globin gene domain. Results. We have demonstrated that in the same cell population the chicken domain of a-globin gene may be organized in two different active chromatin hubs. One of them appears essential for the activation of the a-globin gene expression while the other – for the activation of TMEM8 gene which constitutes a part of the a-globin gene domain in chicken, but not in human and other mammals. Importantly, two regulatory elements participate in the formation of both active chromatin hubs. Conclusions. The assembly of the same genomic area into two alternative chromatin hubs which share some regulatory elements suggests that active chromatin hubs are dynamic rather than static, and that regulatory elements may shuttle between different chromatin hubs. Keywords: active chromatin hub, globin gene, genomic domain, chromosome conformation capture.
format	Article
author	Gavrilov, A.A. Philonenko, E.S. Iarovaia, O.V. Razin, S.V.
spellingShingle	Gavrilov, A.A. Philonenko, E.S. Iarovaia, O.V. Razin, S.V. Dynamic nature of active chromatin hubs Вiopolymers and Cell
author_facet	Gavrilov, A.A. Philonenko, E.S. Iarovaia, O.V. Razin, S.V.
author_sort	Gavrilov, A.A.
title	Dynamic nature of active chromatin hubs
title_short	Dynamic nature of active chromatin hubs
title_full	Dynamic nature of active chromatin hubs
title_fullStr	Dynamic nature of active chromatin hubs
title_full_unstemmed	Dynamic nature of active chromatin hubs
title_sort	dynamic nature of active chromatin hubs
publisher	Інститут молекулярної біології і генетики НАН України
publishDate	2011
url	http://dspace.nbuv.gov.ua/handle/123456789/155440
citation_txt	Dynamic nature of active chromatin hubs / A.A. Gavrilov, E.S. Philonenko, O.V. Iarovaia, S.V. Razin // Вiopolymers and Cell. — 2011. — Т. 27, № 5. — С. 364-368. — Бібліогр.: 17 назв. — англ.
series	Вiopolymers and Cell
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fulltext	Dynamic nature of active chromatin hubs A. A. Gavrilov, E. S. Philonenko, O. V. Iarovaia, S. V. Razin Institute of Gene Biology, RAS 34/5, Vavilova Str., Moscow, Russian Federation, 119334 sergey.v.razin@usa.net Aim. In order to get more information about organization of active chromatin hubs and their role in the regu- lation of gene transcription we have studied the spatial organization of the α-globin gene domain in cultured chicken erythroblasts. Methods. The chromosome conformation capture (3C) protocol was employed to analyze the 3D configuration of the chicken α-globin gene domain. Results. We have demonstrated that in the same cell population the chicken domain of α-globin gene may be organized in two different active chromatin hubs. One of them appears essential for the activation of the α-globin gene expression while the other – for the activation of TMEM8 gene which constitutes a part of the α-globin gene domain in chicken, but not in human and other mammals. Importantly, two regulatory elements participate in the formation of both active chromatin hubs. Conclusions. The assembly of the same genomic area into two alternative chromatin hubs which share some re- gulatory elements suggests that active chromatin hubs are dynamic rather than static, and that regulatory ele- ments may shuttle between different chromatin hubs. Keywords: active chromatin hub, globin gene, genomic domain, chromosome conformation capture. Introduction. Although the mechanism of enhancer action is far from being clear, most of the current models postulate that an enhancer physically interacts with the target promoter, while sometimes it is located a considerable distance away, up to several hundred kilobases. Therefore, the segment of the chromatin fibre that separates the promoter and the enhancer must be looped out. In multigene loci a single enhancer or block of enhancers (locus control region) appears to ac- tivate simultaneously several promoters. For example, in erythroid cells of adult lineage, the mouse β-globin locus control region (LCR) stimulates expression of both the β-major and β-minor globin genes. The pro- moters of these genes are located at a distance of 14 kb from each other and could not simultaneously interact with the same LCR if only a single loop was formed. It was therefore proposed that LCR forms short-living alternating complexes with these promoters [1, 2]. Another model postulates association of an LCR and se- veral depended promoters in an active chromatin hub, a multicomponent complex, from which several chroma- tin segments are looped out [3, 4]. This model, al- though presently widely accepted [3, 4], still remains hypothetical due to the intrinsic limitations of the chro- mosome conformation capture (3C) approach, which can only establish pairwise interactions between dis- tant chromosome elements [5]. Thus, multicomponent chromatin hubs can be only predicted, not proved, ba- sed on the results of 3C analysis. Besides, most of the present knowledge about active chromatin hubs is ba- sed on the studies of one model system, the murine do- main of β-globin genes [4, 6–8]. In order to get more in- sights into the nature of active chromanin hubs we stu- died the spatial organization of the α-globin gene do- main in chicken erythroid cells producing globins of an adult type. The results obtained demonstrate that in this domain two alternative active chromatin hubs may be assembled. Most interesting, two regulatory elements 364 ISSN 0233–7657. Biopolymers and Cell. 2011. Vol. 27. N 5. P. 364–368  Institute of Molecular Biology and Genetics, NAS of Ukraine, 2011 (the –9kb DNase I hypersensitive site (–9 kb DHS) and the downstream enhancer) participate in the formation of both active chromatin hubs. They should thus shuttle between these hubs as predicted by the «flip-flop» mo- del [1, 2]. Materials and methods. Cell culture. The avian erythroblastosis virus-transformed chicken erythro- blast cells HD3 (clone A6 of line LSCC [9]) were grown in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 2 % chicken serum and 8 % fetal bovine serum (FBS) at 37 oC with 5 % CO2. To induce terminal erythroid differentiation, HD3 cells at a density of 1 ⋅ 106 cells/ml were incubated in the above medium additionally containing 10 mM HEPES (pH 8.0) and 20 µM iso-H-7 (1-(5-Isoquinolinylsul- fonyl)-3-methylpiperazine dihydrochloride, «Fluka», Switzerland) at 42 °C in 100 % air atmosphere [10]. The cells were collected in 12 h after the beginning of induction. 3C analysis. 3C analysis was performed as descri- bed [11, 12]. A random-ligation control was generated using DNA of a bacterial artificial chromosome contai- ning the chicken α-globin gene domain along with the flanking areas (Gallus gallus BAC clone CH261- 75C12, CHORI BACPAC Resources Center). The ligation products were analysed using the real- time PCR with TaqMan probes. Primers and TaqMan probes for PCR analysis were designed using the DNA sequence of Gallus gallus BAC clone CH261-75C12 (AC172304, GeneBank) and Primer Premier 5 compu- ter software (PRIMER Biosoft International). The se- quences of the primers and TaqMan probes are avai- lable upon request. Each PCR reaction was carried out in quadruple repetition and the corresponding results were averaged. Once a resulting 3C curve representing the spectrum of interactions between an anchor frag- ment and other fragments throughout the domain was obtained, the experiments starting with living cells we- re repeated twice more in order to check the repro- ducibility of the results. To take into account the differences in the effici- ency of crosslinking/restriction/ligation and in the quantity of DNA in the 3C templates obtained from cells of different types, the internal standard was used [11]. A house-keeping gene ERCC3 situated on another chicken chromosome was chosen as such a standard. Results and discussion. The domain of chicken α- globin genes (Fig. 1, A) contains three alpha-type glo- bin genes and several regulatory elements, including the major regulatory element (MRE) of the domain located in an intron of the apparently house-keeping gene C16orf35, and the downstream enhancer located right after the αA gene. We have demonstrated that this domain also harbors a non-globin gene TMEM8. It was relocated to the vicinity of the α-globin cluster due to the inversion of a ~170-kb genomic fragment. Al- though in humans TMEM8 is preferentially expressed in resting T-lymphocytes, in chickens it acquires an erythroid-specific expression profile and is upregu- lated upon terminal differentiation of erythroblasts [13]. In the intron 7 of chicken TMEM8 gene an ery- throid-specific enhancer is located [13]. AEV-transformed chicken erythroblasts (line HD3, clone A6 of line LSCC) correspond to chicken hemo- poietic cells of the red lineage arrested at early stages of differentiation [9, 14]. They do not express globin ge- nes, although the α-globin gene domain resides in an ac- tive configuration supported by low-level transcription of the whole domain [15]. After induction of terminal erythroid differentiation, HD3 cells stop proliferation and start production of globins. To study the spatial organization of the α-globin gene domain in prolife- rating and differentiated HD3 cells we used the 3C method [5, 8, 16]. The combination of BglII and BamHI restriction enzymes was used for 3C analysis. These enzymes recognize different consensuses but produce compatible DNA ends which can be cross- ligated. We first investigated the interaction of the LCR- like MRE with each of the downstream restriction frag- ments (with the exception of very short fragments). As shown in Fig. 1, B, in both proliferating and differen- tiated HD3 cells this element interacts with the –9 kb DHS, the upstream CpG island of the α-globin gene cluster and the αD gene promoter. In differentiated (i. e. expressing globins) HD3 cells the frequencies of all above-mentioned interactions increased. In addition, a clear interaction between the MRE element and the downstream enhancer was established. Notably, the MRE did not interact with upstream CpG island of TMEM8 gene and with the enhancer located in the body of TMEM8 gene (Fig. 1, B). In contrast, in experiments 365 DYNAMIC NATURE OF ACTIVE CHROMATIN HUBS with the anchor fixed at the –9 DHS or at the down- stream enhancer of the α-globin gene domain the inter- actions with the CpG island of TMEM8 gene and with the enhancer located in the body of TMEM8 gene were clearly visible (Fig. 1, C, D). Again, the apparent fre- quency of the interactions was much more prominent in differentiated HD3 cells. The significance of the abo- ve-described observations was verified in reciprocal 366 GAVRILOV A. A. ET AL. Fig. 1. 3C analysis of the chicken α-globin gene domain: A – the scheme showing positions of important functional elements in the chicken α-globin gene domain (the scale is in kb and «0» point of the scale is arbitrary placed at the 3'-end of the C16orf35 gene); B–F – relative frequencies of cross-linking between the anchor fragments bearing B – MRE; C – –9 kb DHS; D – the downstream enhancer of the α-globin gene domain; E – the upstream CpG island of the TMEM8 gene; F – the erythroid-specific enhancer located in the body of the TMEM8 gene and other fragments of the locus. The x axis shows distances in kb. On the top of each graph a scheme of the domain with the same symbols as in A is shown. The results of 3C analysis for cycling (non-induced) and differentiated (induced) HD3 cells are shown by closed and open circles, respectively. The frequency of cross-linking the fragment bearing MRE with the fragment bearing –9 kb DHS in differentiated HD3 cells was taken to equal 100 relative units. The dark gray rectangle in the background of each graph with the anchor drawn above indicates a fixed (anchor) DNA fragment, and the light gray rectangles – test-fragments. Error bars represent SEM experiments when the anchor was placed on the CpG island of TMEM8 gene and on the enhancer situated in the body of TMEM8 gene (Fig. 1, E, F). Taking together, the results of our 3C analysis can not be explained by the assembly of a single activation complex harboring all known regulatory elements of the α-globin gene domain. There should exist at least two alternative activation complexes stimulating ex- pression of globin genes and of TMEM8 gene (Fig. 2). The «globin hub» includes the MRE, the –9 kb up- stream DHS, the –4 kb upstream CpG island of the α- globin gene domain, the αD gene promoter and the downstream enhancer. The «TMEM8 hub» includes the –9 kb DHS, the downstream enhancer, the upstream CpG island of the TMEM8 gene and the erythroid-spe- cific enhancer located in one of the TMEM8 gene in- trons. Two regulatory elements (the –9 kb DHS and the downstream enhancer) participate in the formation of both active chromatin hubs. They should thus shuttle between these hubs as predicted by the «flip-flop» model [1, 2]. This model was proposed to explain the ability of the β-globin gene domain LCR to activate transcription of several genes which appeared to be transcribed simultaneously. Although this model was never disproved, it was almost forgotten after advan- cement of the active chromatin hub model [4, 6–8, 17]. Indeed, the assembly of several enhancers and promo- ters into a single active chromatin hub suggests a simp- ler explanation for the ability of an enhancer to activate simultaneously several promoters. Our data suggest that the two models are not mu- tually exclusive, and that chromatin hubs should be re- garded as dynamic rather than static. Acknowledgements. This work was supported by the Ministry of Science and Education of the Russian Federation (contracts 16.740.11.0353 and 16.740.11. 0483) and by Russian Foundation for Support of Basic Researches (grants 11-04-00361-а and 11-04-91334- NNIO_а). О. А. Гав ри лов, О. С. Фи ло нен ко, О. В. Яро вая, С. В. Ра зин Ди намічна при ро да ак ти ва тор них хро ма ти но вих блоків Ре зю ме Мета. Щоб от ри ма ти нову інфор мацію сто сов но організації ак- ти ва тор них хро ма ти но вих блоків та їхньої ролі в ре гу ляції транс- крипції ми вив чи ли про сто ро ву організацію до ме ну α-глобіно вих генів у куль ти во ва них ку ря чих ерит роб лас тах. Ме то ди. Для ана - ли зу 3D конфігу рації до ме ну α-глобіно вих генів ви ко рис та но ме - тод фіксації кон фор мації хро мо со ми (3С). Ре зуль та ти. Ми про- де мо нстру ва ли, що в одній і тій самій по пу ляції ку ря чих клітин до мен α-глобіно вих генів може бути організо ва ним у два різних хро ма ти но вих бло ки. Один з них необхідний для ак ти вації транс - крипції α-глобіно вих генів, тоді як дру гий за без пе чує ак ти вацію транс крипції гена TMEM8. Цей ген вхо дить до скла ду до ме ну α- глобіно вих генів ку рей, але не ссавців і лю ди ни. Важ ли во, що два ре гу ля тор них еле мен ти до ме ну α-глобіно вих генів при сутні у скла- ді обох ак ти ва тор них хро ма ти но вих блоків. Вис нов ки. Існу ван ня в од но му й тому ж ге ном но му до мені двох різних ак ти ва тор них ком плексів, які ма ють у своєму складі спільні ре гу ля торні еле мен - ти, свідчить про ди намічну при ро ду ак ти ва тор них хро ма ти но- вих блоків, що доз во ляє спільним ре гу ля тор ним еле мен там періо- дично пе реміщу ва ти ся з од но го ком плек су в дру гий. Клю чові сло ва: ак ти ва торні хро ма ти нові бло ки, глобіно вий ген, ге ном ний до мен, ме тод фіксації хро мо со ми. А. А. Гав ри лов, Е. С. Фи ло нен ко, О. В. Яро вая, С. В. Ра зин Ди на ми чес кая при ро да ак ти ва тор ных хро ма ти но вых бло ков Ре зю ме Цель. Что бы по лу чить но вую ин фор ма цию об орга ни за ции ак ти - ва тор ных хро ма ти но вых бло ков и их роли в ре гу ля ции транс крип - ции, мы из учи ли про стра нствен ную орга ни за цию до ме на α-гло- би но вых ге нов в куль ти ви ру е мых ку ри ных эрит роб лас тах. Ме то - ды. Для ана ли за 3D кон фи гу ра ции до ме на α-гло би но вых ге нов ис - поль зо ван ме тод фик са ции кон фор ма ции хро мо со мы (3С). Ре- зуль та ты. Мы про де мо нстри ро ва ли, что в од ной и той же по пу - ля ции ку ри ных кле ток до мен α-гло би но вых ге нов мо жет быть орга ни зо ван в два раз лич ных хро ма ти но вых бло ка. Один из них не- об хо дим для ак ти ва ции транс крип ции α-гло би но вых ге нов, в то вре мя как дру гой об ес пе чи ва ет ак ти ва цию транс крип ции гена TMEM8. Этот ген вхо дит в со став до ме на α-гло би но вых ге нов кур, но не мле ко пи та ю щих и че ло ве ка. Важ но, что два ре гу ля тор- ных эле мен та до ме на α-гло би но вых ге нов при су тству ют в со - ста ве об оих ак ти ва тор ных хро ма ти но вых бло ков. Вы во ды. Су- щес тво ва ние в од ном и том же ге ном ном до ме не двух раз ных ак - ти ва тор ных ком плек сов, име ю щих в сво ем со ста ве об щие ре гу - ля тор ные эле мен ты, сви де т ельству ет о ди на ми чес кой при ро де ак ти ва тор ных хро ма ти но вых бло ков, что по зво ля ет об щим ре - 367 DYNAMIC NATURE OF ACTIVE CHROMATIN HUBS Fig. 2. Configuration of the two alternative active chromatin hubs described in this article 368 GAVRILOV A. A. ET AL. гу ля тор ным эле мен там пе ри о ди чес ки пе ре ме щать ся из од но го ком плек са в дру гой. Клю че вые сло ва: ак ти ва тор ные хро ма ти но вые бло ки, гло би - но вый ген, ге ном ный до мен, ме тод фик са ции хро мо со мы. REFERENCES 1. Wijgerde M., Grosveld F., Fraser P. Transcription complex sta- bility and chromatin dynamics in vivo // Nature.–1995.–377, N 6546.–P. 209–213. 2. Gribnau J., de Boer E., Trimborn T., Wijgerde M., Milot E., Grosveld F., Fraser P. Chromatin interaction mechanism of transcriptional control in vivo // EMBO J.–1998.–17, N 20.– P. 6020–6027. 3. Palstra R. J., de Laat W., Grosveld F. Beta-globin regulation and long-range interactions // Adv. Genet.–2008.–61.–P. 107– 142. 4. de Laat W., Klous P., Kooren J., Noordermeer D., Palstra R. J., Simonis M., Splinter E., Grosveld F. Three-dimensional organi- zation of gene expression in erythroid cells // Curr. Top. Dev. Biol.–2008.–82.–P. 117–139. 5. Dekker J., Rippe K., Dekker M., Kleckner N. Capturing chromo- some conformation // Science.–2002.–295, N 5558.–P. 1306– 1311. 6. Kooren J., Palstra R. 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Dynamic nature of active chromatin hubs

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