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Action Mechanism of Enhancers for Activating Gene Transcription
Biomed Sci Letters 2023;29:103-108
Published online September 30, 2023;  https://doi.org/10.15616/BSL.2023.29.3.103
© 2023 The Korean Society For Biomedical Laboratory Sciences.

Yea Woon Kim1,* and AeRi Kim2,†,*

1Department of Biomedical Laboratory Science, College of Healthcare Medical Science and Engineering, Inje University, Gimhae Gyeongnam 50834, Korea
2Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Korea
Correspondence to: AeRi Kim. Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Korea.
Tel: +82-51-510-3683, Fax: +82-51-513-9258, e-mail: kimaeri@pusan.ac.kr
*Professor.
Received August 16, 2023; Revised September 21, 2023; Accepted September 22, 2023.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
Enhancers are cis-elements to regulate transcription of cell/tissue-specific genes in multicellular organisms. These elements locate in upstream or downstream regions of target genes and are found in a long distance up to 100 Kb in some cases. Transcription factors and coactivators bind to enhancers in a chromatin environment. Enhancers appear to facilitate the transcription of target genes by communicating with promoters and activating them. As transcription activation mechanism of enhancers, chromatin looping between enhancers and promoters, tracking of enhancer activity to promoters along the intervening regions, and movement of enhancers and promoters into transcription condensates have been suggested based on various molecular and cellular biology studies. These mechanisms are likely to act together rather than exclusive each other for gene transcription. Understanding of enhancer action mechanism may provide a way to regulate the transcription of cell/tissue-specific genes relating with aging or various diseases.
Keywords : Enhancer, Promoter, Looping, Tracking, Transcription condensate
꽌 濡

깮臾쇱 쑀쟾泥(genome)뿉 議댁옱븯뒗 닔留롮 쑀쟾옄뱾씠 諛쒗쁽릺뼱 궡븘媛꾨떎. 떎꽭룷 깮臾쇱쓽 寃쎌슦, 꽭룷쓽 湲곕낯쟻씤 湲곕뒫 쑀吏瑜 쐞빐 븯슦뒪궎븨 쑀쟾옄(housekeeping genes)濡 遺덈━뒗 쑀쟾옄뱾씠 紐⑤뱺 꽭룷뿉꽌 諛쒗쁽릺硫, 諛쒖깮, 꽦옣, 議곗쭅 遺꾪솕 벑쓣 쐞빐꽌 씪遺 쑀쟾옄뱾 듅젙 꽭룷/議곗쭅뿉꽌 諛쒗쁽맂떎. 씠윴 쑀쟾옄뱾쓣 꽭룷/議곗쭅 듅씠쟻 쑀쟾옄뱾(cell/tissue-specific genes)씠씪怨 븯硫, 쟻젅븳 떆湲곗뿉 듅젙 꽭룷뿉꽌留 諛쒗쁽릺뼱빞 븳떎. 씠瑜 쐞빐 쑀쟾옄 諛쒗쁽 議곗젅씠 븘슂븯硫, 媛옣 씪諛섏쟻씤 議곗젅 쟾궗 솢꽦솕 떒怨꾩뿉꽌 씪뼱궃떎. 쑀쟾泥댁뿉뒗 쑀쟾옄 쟾궗 議곗젅 遺쐞(transcriptional regulatory elements)씪뒗 cis-elements媛 議댁옱븯硫, 봽濡쒕え꽣(promoter), 씤빖꽌(enhancer), 씤뒓젅씠꽣(insulator) 벑씠 뿬湲곗뿉 룷븿맂떎. 씠뱾 以 씤빖꽌뒗 꽭룷/議곗쭅 듅씠쟻 쑀쟾옄쓽 쟾궗瑜 쐞빐 븘슂븯硫, 봽濡쒕え꽣 떖由 몴쟻 쑀쟾옄 硫由 뼥뼱졇 議댁옱븯뒗 寃쎌슦媛 留롫떎. 씤빖꽌뒗 꽭룷 궡쇅쓽 떊샇뿉 쓽빐 솢꽦솕릺硫, 몴쟻 쑀쟾옄(target gene)쓽 봽濡쒕え꽣 냼넻(communication)븿쑝濡쒖뜥 쑀쟾옄 쟾궗瑜 쑀룄븳떎.

씤빖꽌뒗 쑀쟾泥댁뿉 궛옱릺뼱 엳뒗 빟 200~400 bp 湲몄씠쓽 DNA 遺쐞濡, 궗엺 쑀쟾泥대 긽쑝濡 吏꾪뻾맂 ENCODE 봽濡쒖젥듃뿉꽌 빟 668,000뿬 媛쒖쓽 遺쐞媛 씤빖꽌濡 異붿젙릺뿀떎(Moore et al., 2020). 吏湲덇퉴吏 諛앺吏 씤빖꽌뱾 몴쟻 쑀쟾옄쓽 긽瑜섏뿭(upstream)씠굹 븯瑜섏뿭(downstream), 洹몃━怨 씤듃濡(intron) 벑 떎뼇븳 쐞移섏뿉 議댁옱븯怨 엳쑝硫, 씤빖꽌쓽 諛⑺뼢(orientation)씠굹 嫄곕━뒗 몴쟻 쑀쟾옄쓽 쟾궗 솢꽦솕뿉 쁺뼢쓣 誘몄튂吏 븡뒗 寃껋쑝濡 蹂댁씤떎(Chien et al., 2011). 씤빖꽌 遺쐞뒗 듅蹂꾪븳 겕濡쒕쭏떞(chromatin) 援ъ“瑜 媛뽮퀬 엳뒗뜲, 몴쟻쑝濡 돱겢젅삤醫(nucleosome) 援ъ“媛 삎꽦릺吏 븡븘꽌 DNase I怨 媛숈 빑궛媛닔遺꾪빐슚냼(nuclease)뿉 쓽빐 돺寃 DNA媛 젅떒맂떎(Fig. 1) (Boyle et al., 2008; Thurman et al., 2012). 씠윴 援ъ“뒗 씤빖꽌 DNA뿉 議댁옱븯뒗 議곗쭅 듅씠쟻 쟾궗씤옄 寃고빀 꽌뿴(transcription factor binding motifs)쓣 끂異쒖떆耳 쟾궗씤옄쓽 젒洹 諛 寃고빀쓣 슜씠븯寃 븯怨, 씠 쟾궗씤옄뱾 엳뒪넠 蹂삎 슚냼(histone modifying enzyme)굹 겕濡쒕쭏떞 怨좊━ 삎꽦 씤옄(looping factor) 媛숈 蹂댁“씤옄뱾(cofactors)쓣 紐⑥쭛븳떎. 씤빖꽌 二쇰쓽 돱겢젅삤醫뿉꽌뒗 듅吏뺤쟻씤 엳뒪넠 蹂삎(modifications)씠 씪뼱굹뒗뜲, 엳뒪넠 H3K4 紐⑤끂硫뷀떥솕(H3K4me1) H3K27 븘꽭떥솕(H3K27ac)媛 몴쟻씠떎(Creyghton et al., 2010). 삉븳 RNA 以묓빀슚냼 II (RNA polymerase II, RNA Pol II)媛 씤빖꽌뿉 寃고빀븯硫, 씠뱾 鍮꾧탳쟻 吏㏃ 湲몄씠쓽 씤빖꽌 RNA (enhancer RNA, eRNA)瑜 쟾궗븳떎(Hah et al., 2013). 理쒓렐뿉뒗 씤빖꽌瑜 씪諛 씤빖꽌(typical enhancer) 뒋띁 씤빖꽌(super enhancer)濡 遺꾨쪟븯湲곕룄 븯뒗뜲, 씪諛 씤빖꽌뒗 븯굹쓽 씤빖꽌媛 떒룆쑝濡 議댁옱븯뒗 寃쎌슦씠硫, 뒋띁 씤빖꽌뒗 뿬윭 媛쒓 紐⑥뿬 吏묐떒(cluster)쓣 삎꽦븯뒗 寃쎌슦씠떎. 뒋띁 씤빖꽌뒗 씪諛 씤빖꽌蹂대떎 쟾궗씤옄 蹂댁“씤옄뱾쓽 寃고빀 젙룄媛 넂쑝硫, 몴쟻 쑀쟾옄쓽 쟾궗瑜 媛뺣젰븯寃 솢꽦솕떆궎뒗 寃껋쑝濡 븣젮졇 엳떎(Whyte et al., 2013).

Fig. 1. Transcription activation by enhancers.
Enhancers are cis-regulatory elements to regulate gene transcription in a long distance. Active enhancers are occupied by transcription factors and coactivators and marked by specific histone modifications such as H3K4me1 and H3K27ac. Enhancer RNA is transcribed from them. Cell/tissue-specific genes are transcriptionally activated by the enhancers.

븵꽌 뼵湲됲븳 寃껋쿂읆 吏湲덇퉴吏 븣젮吏 씤빖꽌쓽 쐞移 諛 몴쟻 쑀쟾옄源뚯쓽 嫄곕━뒗 떎뼇븯떎. 吏㏃ 寃쎌슦뒗 닔 Kb 젙룄씠吏留, 100 Kb뿉 씠瑜대뒗 寃쎌슦룄 엳떎. 씠윭븳 嫄곕━쟻 듅吏뺤 씤빖꽌쓽 옉슜 湲곗옉, 利 뼱뼸寃 硫由 뼥뼱졇 엳뒗 몴쟻 쑀쟾옄瑜 李얘퀬 쟾궗瑜 솢꽦솕떆궎뒗吏뿉 븳 쓽臾몄쓣 젣湲고빐 솕떎. 吏궃 20뿬 뀈 룞븞 ChIP (Chromatin Immunoprecipitation), 3C (Chromosome Confirmation Capture), 꽭룷 씠誘몄쭠(cell imaging), CRISPR-Cas9 湲곕컲쓽 뿬윭 湲곕쾿뱾쓣 씠슜빐꽌 씤빖꽌쓽 옉슜 湲곗옉씠 뿰援щ릺뼱 솕쑝硫, 蹂 珥앹꽕뿉꽌 꽭룷/議곗쭅 듅씠쟻 쑀쟾옄쓽 쟾궗瑜 議곗젅븯湲 쐞븳 씤빖꽌-봽濡쒕え꽣 궗씠쓽 냼넻(communication) 湲곗옉뱾쓣 쑀쟾옄 諛 쑀쟾泥 닔以뿉꽌 꽕紐낇븯怨좎옄 븳떎.

씤빖꽌 봽濡쒕え꽣 궗씠쓽 겕濡쒕쭏떞 怨좊━ 삎꽦(chromatin looping between enhancers and promoters)쓣 넻븳 쑀쟾옄 쟾궗 솢꽦

1980뀈 SV40 씤빖꽌쓽 湲곕뒫씠 蹂닿퀬맂 썑, 씤빖꽌쓽 옉슜 湲곗옉뿉 븳 뿬윭 紐⑤뜽씠 젣떆릺뼱 솕떎(Capecchi, 1980). 洹 以 몴쟻씤 寃껋 씤빖꽌媛 硫由 뼥뼱졇 엳뒗 몴쟻 쑀쟾옄 봽濡쒕え꽣 臾쇰━쟻쑝濡 媛源앷쾶 쐞移섑븯硫 봽濡쒕え꽣瑜 솢꽦솕떆耳 쟾궗瑜 珥됱쭊븯뒗 寃껋씠떎(Fig. 2A). 쓷엳 씤빖꽌 봽濡쒕え꽣 궗씠쓽 겕濡쒕쭏떞 怨좊━ 삎꽦쑝濡 뼵湲됰릺뒗뜲, 씠 湲곗옉 3C 湲곕쾿쓣 궗슜븯뿬 떎뿕쟻쑝濡 利앸챸릺뿀떎. 3C 湲곕쾿 궡븘엳뒗 꽭룷뿉 룷由꾩븣뜲엳뱶瑜 泥섎━븯뿬 빑 궡쓽 겕濡쒕쭏떞쓣 怨좎젙븳 썑, 젣븳슚냼瑜 씠슜븯뿬 DNA瑜 뿬윭 議곌컖쑝濡 옄瑜닿퀬 떎떆 뿰寃고븿쑝濡쒖뜥 빑뿉꽌 씤빖꽌굹 봽濡쒕え꽣 媛숈 듅젙 DNA 遺쐞쓽 엯泥댁쟻 쐞移섎 蹂댁뿬以떎(Dekker et al., 2002; de Wit and de Laat, 2012). 3C 떎뿕쓣 넻빐 뼸 寃곌낵뱾 씤빖꽌 봽濡쒕え꽣媛 臾쇰━쟻쑝濡 媛源앷쾶 쐞移섑븯뒗 諛섎㈃, 洹 궗씠뿉 겮씤 DNA뒗 諛뽰쑝濡 鍮좎졇굹媛 怨좊━ 援ъ“媛 삎꽦맖쓣 젣떆븯怨, 씠젃寃 삎꽦맂 臾쇰━쟻 洹쇱젒꽦 씤빖꽌쓽 솢꽦 諛 湲곕뒫쓣 봽濡쒕え꽣뿉 吏곸젒 쟾떖븯寃 븯뒗 寃껋쑝濡 깮媛곷맂떎(Tolhuis et al., 2002; Spilianakis and Flavell, 2004). 떎젣濡 諛쒖깮 諛 議곗쭅뿉 뵲씪 쟾궗릺뒗 湲濡쒕퉰 쑀쟾옄 醫뚯쐞뿉꽌 씤빖꽌-봽濡쒕え꽣 궗씠쓽 겕濡쒕쭏떞 怨좊━ 援ъ“媛 쑀쟾옄뱾쓽 쟾궗뿉 留욎떠 삎꽦릺뒗 寃껋씠 愿李곕릺뿀떎(Palstra et al., 2003; de Laat and Duboule, 2013).

Fig. 2. Mechanisms of enhancer action.
(A) A chromatin loop is formed between enhancer and promoter by extruding the intervening region, which allows direct interaction of enhancer with promoter of target gene. (B) RNA is transcribed from enhancers to promoters and histone H3K27ac is enriched between enhancers and promoters, which indicate the tracking of enhancer activity along the intervening regions. (C) Transcription condensates are formed by various week interaction among transcription factors, cofactors, and RNA Pol II. Enhancers are likely to convey target genes to transcription condensates where biomolecules for gene transcription are enriched.

겕濡쒕쭏떞 怨좊━ 援ъ“뒗 씤빖꽌 봽濡쒕え꽣뿉 吏곴컙젒쟻쑝濡 寃고빀븯뒗 떒諛깆쭏뱾뿉 쓽빐 삎꽦릺뒗 寃껋쑝濡 蹂댁씤떎. 湲濡쒕퉰 醫뚯쐞쓽 쑀쟾옄뱾 쟻삁援 꽭룷 듅씠쟻쑝濡 쟾궗릺뒗뜲, 씠 醫뚯쐞뿉꽌 닔뻾맂 뿰援щ뱾 씤빖꽌 봽濡쒕え꽣뿉 寃고빀븯뒗 쟾궗씤옄, GATA1, TAL1, KLF1 (Drissen et al., 2004; Vakoc et al., 2005; Yun et al., 2014)씠 겕濡쒕쭏떞 怨좊━ 삎꽦뿉 븘슂븿쓣 蹂댁뿬二쇱뿀떎. GATA1怨 TAL1 LDB1 蹂듯빀泥댁뿉 寃고빀븯뒗뜲, 씠 븣 LDB1씠 씠빀泥(dimer)瑜 삎꽦븯뿬 뿰寃 떎由 뿭븷쓣 븿쑝濡쒖뜥 怨좊━ 援ъ“瑜 삎꽦븳떎(Wadman et al., 1997; Song et al., 2007; Deng et al., 2012; Li et al., 2013a). 삉븳 깮伊 以꾧린꽭룷뿉꽌 吏꾪뻾맂 뿰援щ뒗 YY1씠씪뒗 떒諛깆쭏룄 씤빖꽌 봽濡쒕え꽣뿉 寃고빀븯뿬 씠빀泥대 삎꽦븿쑝濡쒖뜥 怨좊━ 援ъ“ 삎꽦뿉 湲곗뿬븯뒗 寃껋쓣 蹂댁뿬二쇱뿀떎(L처pez-Perrote et al., 2014; Weintraub et al., 2017). 씠쇅뿉 Mediator cohesin 媛숈 떒諛깆쭏뱾룄 씤빖꽌-봽濡쒕え꽣 궗씠쓽 怨좊━ 援ъ“ 삎꽦뿉 愿뿬븯硫, 븵꽌 뼵湲됲븳 eRNA룄 씤빖꽌 봽濡쒕え꽣쓽 寃고빀뿉 븘슂븳 슂냼濡 蹂댁씤떎(Hadjur et al., 2009; Kagey et al., 2010; Li et al., 2013b; Hsieh et al., 2014). 씠젃벏 怨좊━ 援ъ“ 삎꽦 씤빖꽌 봽濡쒕え꽣뿉 寃고빀븯뒗 떒諛깆쭏뱾씠 以묒슂븳 뿭븷쓣 븯뒗 寃껋쑝濡 깮媛곷맂떎. 븯吏留 뼱뼸寃 씤빖꽌媛 癒 嫄곕━뿉 뼥뼱졇 엳뒗 몴쟻 쑀쟾옄쓽 봽濡쒕え꽣瑜 李얠븘궡뒗吏뒗 뿬쟾엳 쓽臾몄씠떎.

씤빖꽌뿉꽌 봽濡쒕え꽣濡 듃옒궧(tracking from enhancers to promoters)쓣 넻븳 쑀쟾옄 쟾궗 솢꽦

듃옒궧 紐⑤뜽 씠由꾩쿂읆 씤빖꽌쓽 솢꽦쓣 몴쟻 쑀쟾옄源뚯 븳 嫄몄쓬 븳 嫄몄쓬뵫 쟾떖븯뒗 寃껋씠떎. 씤빖꽌뿉 寃고빀븳 쟾궗씤옄뱾 RNA Pol II瑜 룷븿븯뒗 쟾궗 湲곌뎄(transcription machinery)瑜 뜲젮삤뒗뜲, 씠 RNA Pol II媛 몴쟻 쑀쟾옄 諛⑺뼢쑝濡 씠룞븯硫댁꽌 씤빖꽌쓽 솢꽦쓣 봽濡쒕え꽣뿉 쟾떖븯뒗 寃껋쑝濡 蹂댁씤떎(Fig. 2B) (Wang et al., 2005; Zhu et al., 2007). RNA Pol II쓽 씠룞 봽濡쒕え꽣 諛⑺뼢쑝濡 noncoding/intergenic RNA瑜 쟾궗븯寃 릺怨, 씠젃寃 깮꽦맂 RNA뒗 鍮꾨줉 mRNA뿉 鍮꾪빐 뼇 쟻吏留, RT-qPCR씠굹 RNA-seq 遺꾩꽍뿉꽌 紐낇솗엳 솗씤맂떎. 삉븳 엳뒪넠 븘꽭떥솕 슚냼媛 RNA Pol II 寃고빀븯뿬 븿猿 씠룞븯뒗 寃껋쑝濡 깮媛곷릺硫, 洹 寃곌낵 씤빖꽌 봽濡쒕え꽣 궗씠 吏뿭뿉꽌 넂 닔以쓽 엳뒪넠 븘꽭떥솕媛 씪뼱궃떎(Hatzis and Talianidis, 2002; Zhu et al., 2007). 씤빖꽌 봽濡쒕え꽣 궗씠 吏뿭쓽 RNA 쟾궗 諛 엳뒪넠 븘꽭떥솕뒗 湲濡쒕퉰 醫뚯쐞瑜 룷븿븳 뿬윭 쑀쟾옄 醫뚯쐞뿉꽌 愿李곕릺뿀쑝硫, 理쒓렐 RNA-seq怨 ChIP-seq쓣 씠슜븳 쑀쟾泥 닔以쓽 뿰援щ룄 씤빖꽌 異붿젙 몴쟻 쑀쟾옄 궗씠뿉꽌 뿰냽쟻씤 엳뒪넠 H3K27ac RNA 쟾궗瑜 蹂댁뿬二쇱뿀떎(Kim et al., 2023). 씠젃寃 뿰냽쟻씤 엳뒪넠 븘꽭떥솕 RNA 쟾궗뒗 븘꽭떥솕 슚냼 紐⑥쭛뿉 愿뿬븯뒗 쟾궗씤옄瑜 젣嫄고븯嫄곕굹 씤빖꽌 봽濡쒕え꽣 궗씠뿉 씤뒓젅씠꽣瑜 궫엯븿쑝濡쒖뜥 뼲젣맆 닔 엳뒗뜲, 씠윭븳 蹂솕뒗 몴쟻 쑀쟾옄쓽 쟾궗瑜 媛먯냼떆궡쑝濡쒖뜥 듃옒궧뿉 쓽븳 씤빖꽌 솢꽦 쟾떖 湲곗옉쓣 뮮諛쏆묠븳떎(Zhu et al., 2007; Kim et al., 2023).

씤빖꽌쓽 옉슜 湲곗옉쑝濡쒖꽌 듃옒궧 紐 媛吏 臾몄젣젏씠 엳떎. 씤빖꽌媛 몴쟻 쑀쟾옄쓽 泥 踰덉㎏ 씤듃濡좎뿉 쐞移섑븯嫄곕굹 떎瑜 쑀쟾옄瑜 嫄대꼫쎇뼱 몴쟻 쑀쟾옄뿉 룄떖빐빞 븯뒗 寃쎌슦뒗 듃옒궧쑝濡 씤빖꽌쓽 솢꽦쓣 쟾떖븯湲 뼱졄떎. 뵲씪꽌 듃옒궧 옉슜 몴쟻 봽濡쒕え꽣媛 鍮꾧탳쟻 媛源뚯슫(1~10 Kb) 씤빖꽌뿉 븳젙맆 寃껋쑝濡 깮媛곷맂떎. 떎젣濡 듃옒궧 湲곗옉씠 젣떆맂 궗엺 琯-湲濡쒕퉰 쑀쟾옄(10 Kb) HNF-4慣 쑀쟾옄(6.6 Kb)뒗 겕濡쒕쭏떞 怨좊━ 삎꽦쑝濡 솢꽦솕릺뒗 쑀쟾옄뱾蹂대떎 媛源뚯슫 嫄곕━뿉 씤빖꽌瑜 媛뽮퀬 엳뿀怨(Hatzis and Talianidis, 2002; Zhu et al., 2007), 쑀쟾泥 닔以쓽 뿰援ъ뿉꽌룄 씤빖꽌 몴쟻 쑀쟾옄媛 媛源뚯씠 엳뒗(룊洹 5 Kb) 寃쎌슦 듃옒궧쓽 듅吏뺣뱾씠 슌졆븯寃 굹궃떎(Kim et al., 2023). 삉븳 떇꽭룷(macrophages)뿉꽌 LPS 옄洹뱀뿉 쓽빐 쑀룄맂 옞옱쟻 씤빖꽌뱾(latent enhancers)쓣 遺꾩꽍븳 뿰援щ뒗 옞옱쟻 씤빖꽌뱾 以 留롮 寃껊뱾씠 몴쟻 쑀쟾옄濡쒕꽣 1~10 Kb 븞뿉 쐞移섑븯怨 엳쓬쓣 蹂댁뿬二쇱뿀떎(Ostuni et al., 2013). 吏湲덇퉴吏 씤빖꽌쓽 옉슜 湲곗옉뿉 븳 뿰援щ뒗 몴쟻 쑀쟾옄媛 硫由 뼥뼱졇엳뒗 寃쎌슦뿉 吏묒쨷맂 寃쏀뼢씠 엳뿀怨, 洹 寃곌낵 겕濡쒕쭏떞 怨좊━ 삎꽦뿉 븳 뿰援ш 留롮씠 닔뻾릺뿀떎. 븯吏留 씤빖꽌媛 긽쟻쑝濡 媛源뚯씠 議댁옱븯뒗 寃쎌슦뒗 듃옒궧씠 二쇱슂 湲곗옉씪 닔 엳쑝硫, 뜑 留롮 뿰援ш 븘슂븳 寃껋쑝濡 깮媛곷맂떎.

쟾궗 怨듭옣/쟾궗 쓳異뺣Ъ(transcription factories/transcription condensates)濡 씠룞뿉 쓽븳 씤빖꽌쓽 쑀쟾옄 쟾궗 솢꽦

븵꽌 뼵湲됲븳 씤빖꽌-봽濡쒕え꽣 궗씠쓽 怨좊━ 삎꽦怨 듃옒궧 湲곗옉 二쇰줈 븯굹쓽 씤빖꽌 洹몄쓽 몴쟻 쑀쟾옄瑜 긽쑝濡 꽕紐낇븯怨 엳떎. 洹몃윭굹 떎젣 꽭룷쓽 빑뿉뒗 留롮 닔쓽 씤빖꽌 쑀쟾옄뱾씠 議댁옱븯硫, 씠뱾씠 븿猿 紐⑥뿬 긽샇옉슜븿쑝濡쒖뜥 솢꽦솕맆 닔 엳떎. 씠寃껋 쟾궗 怨듭옣(transcription factories/foci)씠씪뒗 媛쒕뀗쑝濡 꽕紐낅릺뼱 솕뒗뜲, 媛숈 쟾궗씤옄瑜 븘슂濡 븯뒗 뿬윭 씤빖꽌 쑀쟾옄뱾씠 빑쓽 듅젙 援ъ뿭쑝濡 紐⑥씠寃 릺怨, 뿬湲곗뿉 쟾궗씤옄굹 RNA Pol II 벑 쟾궗뿉 븘슂븳 떒諛깆쭏뱾씠 怨좊냽룄濡 議댁옱븿쑝濡쒖뜥 eRNA굹 mRNA 쟾궗瑜 슚쑉쟻쑝濡 珥됱쭊븷 닔 엳寃 븯뒗 寃껋씠떎(Papantonis and Cook, 2013). 떎젣濡 쁽誘멸꼍쓣 씠슜븳 씠誘몄쭠(imaging) 湲곕쾿쑝濡 꽭룷瑜 愿李고뻽쓣 븣 꽭룷 떦 닔諛 媛쒖쓽 쟾궗 怨듭옣씠 愿李곕릺뒗뜲, 씠뒗 븯굹쓽 꽭룷뿉꽌 쟾궗릺뒗 쑀쟾옄 닔(왂 10,000媛) 鍮꾧탳뻽쓣 븣 썾뵮 쟻 닽옄씠떎(Jackson et al., 1998; Osborne et al., 2004). 씠뱾 쟾궗 怨듭옣뿉뒗 쟾궗媛 씪뼱굹뒗 쑀쟾옄뱾씠 紐⑥뿬 엳쑝硫, 쑀쟾옄뱾쓽 씠룞뿉 쓽빐 씠誘 삎꽦맂 쟾궗 怨듭옣씠 쑀吏릺뒗 寃껋쑝濡 깮媛곷맂떎(Osborne et al., 2004). 씠븣 씤빖꽌뒗 쑀쟾옄瑜 쟾궗 怨듭옣쑝濡 씠룞떆궎뒗 뿭븷쓣 떞떦븯뒗 寃껋쑝濡 蹂댁씠뒗뜲, 꽌濡 떎瑜 뿼깋泥댁뿉 쐞移섑븯뒗 쟻삁援 듅씠쟻 쑀쟾옄뱾씠 씤빖꽌뿉 寃고빀븯뒗 議곗쭅 듅씠쟻 쟾궗씤옄 KLF1뿉 쓽빐 븿猿 쟾궗 怨듭옣쑝濡 씠룞븯뒗 寃껋씠 愿李곕릺湲곕룄 븯떎(Schoenfelder et al., 2010).

理쒓렐 쟾궗 怨듭옣 븸泥-븸泥 긽 遺꾨━(liquid-liquid phase separation) 媛쒕뀗씠 異붽릺뼱 쟾궗 쓳異뺣Ъ(transcription condensates)濡 諛쒖쟾븯떎(Fig. 2C) (Hnisz et al., 2017). 븸泥-븸泥 긽 遺꾨━ 湲곗옉 씠쟾遺꽣 븣젮졇 솕뜕 꽭룷 궡 깮泥대텇옄 쓳異뺣Ъ(biomolecular condensates)씠 쑀쟾옄 쟾궗, 꽭룷二쇨린, 빆긽꽦怨 媛숈 깮紐낇쁽긽뿉 뿭븷쓣 닔뻾븳떎뒗 寃껋뿉꽌 떆옉븯怨, 理쒓렐 留롮 愿떖怨 븿猿 솢諛쒗븳 뿰援ш 吏꾪뻾릺怨 엳떎. 쟾궗 쓳異뺣Ъ씠 깮泥대텇옄뱾씠 IDR (intrinsic disorder regions)쓣 넻빐 빟븳 寃고빀(닔냼寃고빀, 諛섎뜲瑜대컻뒪옒, 냼닔꽦寃고빀, 洹뱀꽦寃고빀 벑)쓣 삎꽦븯硫댁꽌 긽 遺꾨━媛 씪뼱굹뒗 寃껋쑝濡 씉궗 쟾궗 怨듭옣怨 鍮꾩듂븯떎. 쟾궗 쓳異뺣Ъ 삎꽦뿉뒗 Oct4, Mediator, CTCF 媛숈 쟾궗 愿젴 떒諛깆쭏怨 eRNA瑜 룷븿븳 뿬윭 醫낅쪟쓽 RNA媛 愿뿬븯뒗 寃껋쑝濡 蹂댁씠硫, 씠뱾 紐⑤몢 쟾궗뿉 븘슂븳 슂냼뱾씠떎(Boija et al., 2018; Cho et al., 2018; Henninger et al., 2021; Lee et al., 2021; Lee et al., 2022). 듅엳 쟾궗씤옄뱾 以묒뿉뒗 IDR쓣 媛뽮퀬 엳뒗 寃쎌슦媛 엳뒗뜲, 씤빖꽌뿉 寃고빀븳 쟾궗씤옄뱾씠 쓳異뺣Ъ 삎꽦뿉 湲곗뿬븯怨, 異붽쟻쑝濡 씤빖꽌뱾쓣 걣뼱뱾씠뒗 寃껋쑝濡 깮媛곷맂떎. 씠젃寃 쑀쟾옄 솢꽦쓣 쐞빐 씤빖꽌 봽濡쒕え꽣쓽 吏곸젒쟻씤 寃고빀씠 瑗 븘슂븳 寃껋 븘땲떎. 理쒓렐 궡븘엳뒗 꽭룷 씠誘몄쭠 삉뒗 3D-SIM (3D-structured illumination microscopy) 湲곗닠쓣 씠슜븯뿬 Sox2 쑀쟾옄 씤빖꽌瑜 궡렣蹂 寃곌낵, 씠뱾씠 븘二 媛源앷쾶 쐞移섑븯怨 엳吏뒗 븡븯湲 븣臾몄씠떎(Alexander et al., 2019; Benabdallah et al., 2019). 씠윴 援ы쉷 삎꽦쓣 넻빐 씤빖꽌媛 醫 뜑 돺寃 몴쟻 쑀쟾옄瑜 李얘퀬, 紐⑥뿬엳뒗 쟾궗 愿젴 떒諛깆쭏뱾쓣 슚쑉쟻쑝濡 궗슜븷 닔 엳쓣 寃껋쑝濡 깮媛곷맂떎.

寃 濡

吏湲덇퉴吏 3媛吏 씤빖꽌쓽 옉슜 湲곗옉뿉 빐 궡렣遊ㅻ떎. 씠 湲곗옉뱾 꽌濡 떎瑜 떎뿕 湲곕쾿뿉 쓽빐 젣떆릺뿀쑝硫, 뿰援ъ뿉 궗슜맂 쑀쟾옄 醫뚯쐞룄 떎瑜대떎. 뵲씪꽌 젣떆맂 湲곗옉뱾씠 꽌濡 諛고쟻씤 寃껋 븘땲硫, 삤엳젮 븿猿 옉슜븷 닔 엳쓣 寃 媛숇떎. 씤빖꽌媛 듃옒궧쑝濡 봽濡쒕え꽣瑜 李얠 썑, 씠뱾 궗씠뿉 겕濡쒕쭏떞 怨좊━ 援ъ“瑜 삎꽦븷 닔룄 엳怨, 씤빖꽌 쑀쟾옄媛 쟾궗 쓳異뺣Ъ 븞쑝濡 씠룞븳 썑, 듃옒궧씠굹 怨좊━ 援ъ“ 삎꽦씠 씪뼱궇 닔룄 엳쓣 寃껋씠떎. 뼱뒓 湲곗옉쓣 궗슜븯뱺 씤빖꽌뒗 꽭룷/議곗쭅 듅씠쟻 쑀쟾옄쓽 쟾궗뿉 븘닔쟻씤 슂냼씠硫, 洹 湲곕뒫씠 쟻젅븳 꽭룷/議곗쭅뿉꽌 솢꽦솕릺뼱 몴쟻 쑀쟾옄뿉 쟾떖릺뼱빞 븳떎. 씠 怨쇱젙씠 젣濡 씪뼱굹吏 븡쑝硫 쑀쟾옄 諛쒗쁽뿉 臾몄젣媛 깮湲곌퀬, 諛쒖깮 諛 遺꾪솕뿉 쁺뼢쓣 誘몄튌 寃껋씠떎. 삉븳 젙룄뿉 뵲씪꽌 吏덈퀝쓣 씪쑝궗 닔룄 엳떎. 洹 몴쟻씤 삁濡 吏以묓빐꽦 鍮덊삁(棺-thalassemia)怨 떎吏利앹씠 엳떎. 吏以묓빐꽦 鍮덊삁 棺-湲濡쒕퉰 쑀쟾옄쓽 씤빖꽌씤 LCR (locus control regions)뿉 寃곗떎怨 媛숈 룎뿰蹂씠媛 諛쒖깮븯뿬 쑀쟾옄 쟾궗媛 씪뼱굹吏 紐삵븯怨, 洹몃줈 씤빐 棺-湲濡쒕퉰 뤃由ы렔씠뱶媛 援ъ꽦 꽦遺꾩씤 뿤紐④濡쒕퉰 떒諛깆쭏씠 젙긽쟻쑝濡 빀꽦릺吏 븡븘 鍮덊삁 利앹긽씠 굹궃떎(Thein et al., 2009). 떎吏利앸룄 Sonic hedgehog (Shh) 쑀쟾옄쓽 씤빖꽌씤 ZRS (zone of polarizing activity regulatory sequence)쓽 룎뿰蹂씠濡 諛쒖깮븯뒗 뙏떎由 湲고삎쓽 븳 醫낅쪟씠떎(Lettice et al., 2003). 뵲씪꽌 씤빖꽌쓽 옉슜 湲곗옉쓣 醫 뜑 뿰援ы븯怨 씠빐븯뒗 寃껋씠 븘슂븯硫, 씠뒗 뿰援щ굹 移섎즺 紐⑹쟻쓽 쑀쟾옄 쟾궗 솢꽦솕 삉뒗 뼲젣瑜 쑀룄븯뒗뜲 솢슜맆 닔 엳쓣 寃껋씠떎.

ACKNOWLEDGEMENT

This work was supported by a 2-Year Research Grant of Pusan National University.

CONFLICT OF INTEREST

The authors have declared no conflict of interest.

References
  1. Alexander JM, Guan J, Li B, et al. Live-cell imaging reveals enhancer-dependent Sox2 transcription in the absence of enhancer proximity. Elife. 2019. 8: e41769.
    Pubmed KoreaMed CrossRef
  2. Benabdallah NS, Williamson I, Illingworth RS, et al. Decreased enhancer-promoter proximity accompanying enhancer activation. Mol Cell. 2019. 76: 473-484.
    Pubmed KoreaMed CrossRef
  3. Boija A, Klein IA, Sabari BR, et al. Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell. 2018. 175: 1842-1855.
    Pubmed KoreaMed CrossRef
  4. Boyle AP, Davis S, Shulha HP, et al. High-resolution mapping and characterization of open chromatin across the genome. Cell. 2008. 132: 311-322.
    Pubmed KoreaMed CrossRef
  5. Capecchi MR. High efficiency transformation by direct microinjection of DNA into cultured mammalian cells. Cell. 1980. 22: 479-488.
    Pubmed CrossRef
  6. Chien R, Zeng W, Kawauchi S, et al. Cohesin mediates chromatin interactions that regulate mammalian 棺-globin expression. J Biol Chem. 2011. 286: 17870-17878.
    Pubmed KoreaMed CrossRef
  7. Cho WK, Spille JH, Hecht M, et al. Mediator and RNA polymerase II clusters associate in transcription-dependent condensates. Science. 2018. 361: 412-415.
    Pubmed KoreaMed CrossRef
  8. Creyghton MP, Cheng AW, Welstead GG, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010. 107: 21931-21936.
    Pubmed KoreaMed CrossRef
  9. de Laat W, Duboule D. Topology of mammalian developmental enhancers and their regulatory landscapes. Nature. 2013. 502: 499-506.
    Pubmed CrossRef
  10. de Wit E, de Laat W. A decade of 3C technologies: insights into nuclear organization. Genes Dev. 2012. 26: 11-24.
    Pubmed KoreaMed CrossRef
  11. Dekker J, Rippe K, Dekker M, Kleckner N. Capturing chromosome conformation. Science. 2002. 295: 1306-1311.
    Pubmed CrossRef
  12. Deng W, Lee J, Wang H, et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell. 2012. 149: 1233-1244.
    Pubmed KoreaMed CrossRef
  13. Drissen R, Palstra RJ, Gillemans N, et al. The active spatial organization of the 棺-globin locus requires the transcription factor EKLF. Genes Dev. 2004. 18: 2485-2490.
    Pubmed KoreaMed CrossRef
  14. Hadjur S, Williams LM, Ryan NK, et al. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature. 2009. 460: 410-413.
    Pubmed KoreaMed CrossRef
  15. Hah N, Murakami S, Nagari A, Danko CG, Kraus WL. Enhancer transcripts mark active estrogen receptor binding sites. Genome Res. 2013. 23: 1210-1223.
    Pubmed KoreaMed CrossRef
  16. Hatzis P, Talianidis I. Dynamics of enhancer-promoter communication during differentiation-induced gene activation. Mol Cell. 2002. 10: 1467-1477.
    Pubmed CrossRef
  17. Henninger JE, Oksuz O, Shrinivas K, et al. RNA-mediated feedback control of transcriptional condensates. Cell. 2021. 184: 207-225.
    Pubmed KoreaMed CrossRef
  18. Hnisz D, Shrinivas K, Young RA, Chakraborty AK, Sharp PA. A phase separation model for transcriptional control. Cell. 2017. 169: 13-23.
    Pubmed KoreaMed CrossRef
  19. Hsieh CL, Fei T, Chen Y, et al. Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc Natl Acad Sci U S A. 2014. 111: 7319-7324.
    Pubmed KoreaMed CrossRef
  20. Jackson DA, Iborra FJ, Manders EM, Cook PR. Numbers and organization of RNA polymerases, nascent transcripts, and transcription units in HeLa nuclei. Mol Biol Cell. 1998. 9: 1523-1536.
    Pubmed KoreaMed CrossRef
  21. Kagey MH, Newman JJ, Bilodeau S, et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010. 467: 430-435.
    Pubmed KoreaMed CrossRef
  22. Kim YW, Kang J, Kim A. Hematopoietic/erythroid enhancers activate nearby target genes by extending histone H3K27ac and transcribing intergenic RNA. FASEB J. 2023. 37: e22870.
    Pubmed CrossRef
  23. Lee JH, Wang R, Xiong F, et al. Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation. Mol Cell. 2021. 81: 3368-3385.
    Pubmed KoreaMed CrossRef
  24. Lee R, Kang MK, Kim YJ, et al. CTCF-mediated chromatin looping provides a topological framework for the formation of phase-separated transcriptional condensates. Nucleic Acids Res. 2022. 50: 207-226.
    Pubmed KoreaMed CrossRef
  25. Lettice LA, Heaney SJH, Purdie LA, et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet. 2003. 12: 1725-1735.
    Pubmed CrossRef
  26. Li L, Freudenberg J, Cui K, et al. Ldb1-nucleated transcription complexes function as primary mediators of global erythroid gene activation. Blood. 2013a. 121: 4575-4585.
    Pubmed KoreaMed CrossRef
  27. Li W, Notani D, Ma Q, et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature. 2013b. 498: 516-520.
    Pubmed KoreaMed CrossRef
  28. L처pez-Perrote A, Alatwi HE, Torreira E, et al. Structure of Yin Yang 1 oligomers that cooperate with RuvBL1-RuvBL2 ATPases. J Biol Chem. 2014. 289: 22614-22629.
    Pubmed KoreaMed CrossRef
  29. Moore JE, Purcaro MJ, Pratt HE, et al. Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature. 2020. 583: 699-710.
  30. Osborne CS, Chakalova L, Brown KE, et al. Active genes dynamically colocalize to shared sites of ongoing transcription. Nat Genet. 2004. 36: 1065-1071.
    Pubmed CrossRef
  31. Ostuni R, Piccolo V, Barozzi I, et al. Latent enhancers activated by stimulation in differentiated cells. Cell. 2013. 152: 157-171.
    Pubmed CrossRef
  32. Palstra RJ, Tolhuis B, Splinter E, Nijmeijer R, Grosveld F, de Laat W. The 棺-globin nuclear compartment in development and erythroid differentiation. Nat Genet. 2003. 35: 190-194.
    Pubmed CrossRef
  33. Papantonis A, Cook PR. Transcription factories: genome organization and gene regulation. Chem Rev. 2013. 113: 8683-8705.
    Pubmed CrossRef
  34. Schoenfelder S, Sexton T, Chakalova L, et al. Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. Nat Genet. 2010. 42: 53-61.
    Pubmed KoreaMed CrossRef
  35. Song SH, Hou C, Dean A. A positive role for NLI/Ldb1 in long-range 棺-globin locus control region function. Mol Cell. 2007. 28: 810-822.
    Pubmed KoreaMed CrossRef
  36. Spilianakis CG, Flavell RA. Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nat Immunol. 2004. 5: 1017-1027.
    Pubmed CrossRef
  37. Thein SL, Wood WG. The molecular basis of 棺-thalassemia, 灌棺-thalassemia, and hereditary persistence of fetal hemoglobin. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge: Cambridge University Press. 2009: 323-356.
    CrossRef
  38. Thurman RE, Rynes E, Humbert R, et al. The accessible chromatin landscape of the human genome. Nature. 2012. 489: 75-82.
  39. Tolhuis B, Palstra RJ, Splinter E, Grosveld F, de Laat W. Looping and interaction between hypersensitive sites in the active 棺-globin locus. Mol Cell. 2002. 10: 1453-1465.
    Pubmed CrossRef
  40. Vakoc CR, Letting DL, Gheldof N, et al. Proximity among distant regulatory elements at the 棺-globin locus requires GATA-1 and FOG-1. Mol Cell. 2005. 17: 453-462.
    Pubmed CrossRef
  41. Wadman IA, Osada H, Gr체tz GG, et al. The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. EMBO J. 1997. 16: 3145-3157.
    Pubmed KoreaMed CrossRef
  42. Wang Q, Carroll JS, Brown M. Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol Cell. 2005. 19: 631-642.
    Pubmed CrossRef
  43. Weintraub AS, Li CH, Zamudio AV, et al. YY1 is a structural regulator of enhancer-promoter loops. Cell. 2017. 171: 1573-1588.
    Pubmed KoreaMed CrossRef
  44. Whyte WA, Orlando DA, Hnisz D, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013. 153: 307-319.
    Pubmed KoreaMed CrossRef
  45. Yun WJ, Kim YW, Kang Y, Lee J, Dean A, Kim A. The hematopoietic regulator TAL1 is required for chromatin looping between the 棺-globin LCR and human 款-globin genes to activate transcription. Nucleic Acids Res. 2014. 42: 4283-4293.
    Pubmed KoreaMed CrossRef
  46. Zhu X, Ling J, Zhang L, Pi W, Wu M, Tuan D. A facilitated tracking and transcription mechanism of long-range enhancer function. Nucleic Acids Res. 2007. 35: 5532-5544.
    Pubmed KoreaMed CrossRef