. 1. 연구의필요성 오토파지는종간에잘보존된자가포식작용으로영양분결핍, 대사성스트레스, 감염, 노화, 암, 퇴행성뇌질환발병등의신호에대해세포의생존및항상성 유지를위하여활성화되는필수적기작이다. 특히세포가영양분결핍상황에노출되었을경우오토파지를통해세포내 불필요한구성요소및소기관을분해

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1 보도자료 암치료에필수적인오토파지 ( 자가포식 ) 조절신호최초규명 - 오토파지의신호조절을통한신개념치료제개발가능성열어 - ( ) *( ). ( ) ( ),

2 . 1. 연구의필요성 오토파지는종간에잘보존된자가포식작용으로영양분결핍, 대사성스트레스, 감염, 노화, 암, 퇴행성뇌질환발병등의신호에대해세포의생존및항상성 유지를위하여활성화되는필수적기작이다. 특히세포가영양분결핍상황에노출되었을경우오토파지를통해세포내 불필요한구성요소및소기관을분해하여필요한에너지원으로재생산하여 체내의다양한스트레스를극복하는기능을수행한다. 오토파지는스트레스상황에신속하게대처해야하는기작으로알려져왔기 때문에현재까지의연구는대부분세포질에서오토파지단백질들이어떻게 결합하고기능하는지에초점이맞춰져있었고핵내에서일어나는유전자발현 및전사 * 조절에대한연구는전무한상황이었다. 이에본연구에서는오토파지의후성유전적 * 및전사조절기전에핵심적인 단백질을찾고그기능을연구하였으며이를통해암및퇴행성뇌질환치료제 개발을위한기반을마련하고자하였다. 2. 연구내용 연구팀은오토파지기능에있어핵내에서의유전자발현에의한조절이중요할 것으로판단하였고특히히스톤단백질 * 의후성유전적인조절이필수적일것으로 예상하였다. 이러한가정에기반하여다양한영양분결핍상황에서히스톤단백질의변형을 관찰한결과히스톤 H3 의아르기닌 17 번잔기에메틸화 * 가유도됨을확인하였고 이러한메틸화를유도하는 CARM1*(coactivator-associated arginine methyltransferase 1) 효소의단백질양또한증가되는것을관찰하였다

3 CARM1 단백질복합체정제를통해정상상황에서는 SKP2-SCF E3 유비퀴틴화 효소 * 에의해 CARM1 단백질이분해되지만영양분결핍상황에서는 SKP2 의 전사가감소되어 CARM1 단백질이분해되지않고안정화되는것을확인하였다. 특히세포에당결핍상황이지속될경우 AMPK*(AMP-activated protein kinase) 인산화효소가활성화되면서 FOXO3* 라는전사인자를인산화시키고 인산화된 FOXO3 는 SKP2 의전사과정을저해함으로써 CARM1 단백질이 안정화된다는것을규명하였다. 안정화된 CARM1 단백질은히스톤 H3 아르기닌 17 번잔기의메틸화를 유도하면서 TFEB*(Transcription factor EB) 이라는전사인자와결합하여 다양한오토파지및라이소좀유전자들의발현을조절하게됨으로써오토파지를 유도하는것을확인하였다. 이렇게새롭게발굴한 AMPK-SKP2-CARM1 로연결되는신호전달경로가 오토파지가유도되는상황에서필수적인신호전달경로임을최초로규명하는데 성공하였다. 3. 연구성과 오토파지를유도하는다양한신호에의해 CARM1 단백질이안정화되고핵내에서히스톤아르기닌잔기의메틸화가유도됨에따라핵심적인오토파지유전자들의발현을조절할수있다는사실을규명하였다. 히스톤아르기닌메틸화를저해하는저해제인엘라그산 (Ellagic acid)* 은베리류에서많이검출되는화학물질로, 말라리아치료제로사용되고있다. 동연구를통해서오토파지유도에중요한히스톤의아르기닌잔기의메틸화를억제함으로써후성유전적조절을하는것을확인하였고이러한엘라그산의효과를마우스모델을이용한실험을통해검증하였다

4 이번연구는핵내에서일어나는오토파지의중요한신호전달경로를발굴하고 여기에핵심적인 CARM1 단백질을발견하여오토파지의후성유전및전사조절 기전을세계최초로규명해서이분야의난제를해결함과동시에새로운연구 분야를개척하는공헌을하였다.,. < > : 이자료에대하여더욱자세한내용을원하시면미래창조과학부김진현사무관 ( ) 에게연락주시기바랍니다

5 연구결과개요 1. ㅇ.. ㅇ. ㅇ,.. 2. ㅇ

6 ㅇ, H3 17. CARM1. ㅇ CARM1 (LC3) (GFP-LC3)* (autophagosome)*. CARM1. polyphenol (Ellagic acid). ㅇ CARM1. CARM1. CARM1 CARM1 SKP2 SCF-E3 F-box. SKP2 CARM1 SKP2 CARM

7 ㅇ SKP2. AMPK SKP2. AMPK ( AMPK). AMPK FOXO3a AMPK FOXO3a SKP2. SKP2 CARM1. ㅇ CARM1 WT Carm1 RNA-sequencing*/ ChIP-sequencing*. CARM1. ㅇ CARM1 TFEB TFEB CARM1 (coactivator). ㅇ CARM1 (in vivo),. CARM1 LC3. (ellagic acid) LC3. CARM

8 3. ㅇ, CARM1.. ㅇ H3 17 CARM1 (Ellagic acid)

9 연구이야기,... CARM1. CARM1 CARM1 knock-in CARM1. CARM1 H3 17 RNA-seq ChIP-seq. CARM1 CARM1....,... CARM

10 . CARM1..,, CARM1.. Nature 1. revision

11 용어설명 1. (Nature) 誌 Thomson JCR (impact factor) Autophagy (, ), 3. (Epigenetics) (genetics) DNA, DNA. DNA (epigenetics). DNA DNA, DNA, (modification). DNA DNA. 3. AMPK (AMP-activated protein kinase) 4. SKP2 SCFs (SKP1-cullin-F-box) E3 F-box 5. CARM1 H Ellagic acid H3 17 polyphenol

12 그림설명 1. CARM1 Carm1 Knock-out(KO) Knock-in(KI) CARM1. : (autolysosome), : (autophagosome), : (multilamellar body)

13 2. CARM

14 3. CARM1 CARM1 SKP2, SKP2 CARM

15 백성희 [ 교신저자 ] 이력사항 1. : : sbaek@snu.ac.kr : : : ( ) 美 University of San Diego, Post-doc 美 University of San Diego, ( ) ( ) ( ) 2013, (2015) 2014 ( ) (2014) 2012 (2012)

16 1. Shin, H-J., Kim H.K., Oh, S.R., Lee, J-G., Kee, M.J., Ko, H-J., Kweon, M-N., Won, K.J., and Baek, S.H. (2016) AMPK-Skp2-CARM1 Signaling Cascade in Transcriptional Regulation of Autophagy. Nature (in press) 2. Hur, J., Choi, J-I., Lee, H., Nham, P., Kim, T-W., Chae, C-W., Yun, J-Y., Kang, J-A., Kang, J., Lee, S.E., Yoon, C-H., Boo, K., Ham, S., Roh, T-Y., Jun, J.K., Lee, H., Baek, S.H. *, and Kim, H-S. * (2016) KAI1 maintains dormancy of long-term hematopoietic stem cells through interaction with DARC-expressing macrophage. Cell Stem Cell DOI: /j.stem (*co-corresponding author) 3. Kim, Y., Nam, H.J., Lee, J., Park, D.Y., Kim, C., Yu, Y.S., Kim, D., Park S.W., Bhin, J., Hwang, D., Lee, H., Koh, G.Y., and Baek, S.H. (2016) Methylation-dependent Regulation of HIF-1α Stability Restricts Retinal and Tumour ngiogenesis. Nature Communications DOI: /ncomms Boo, K.J., Bhin, J.H., Jeon, Y., Kim, J.M., Shin, H.J., Park, J.E., Kim, K.K., Kim, C.R., Jang, H.C., Kim, I.H., Kim, V.N., Hwang, D.H.*, Lee, H.*, and Baek, S.H.* (2015) Pontin Functions As an Essential Coactivator for Oct4-Dependent LincRNA expression in Mouse Embryonic Stem Cells. Nature Communications DOI: /ncomms7810. (*co-corresponding author) 5. Nam, H.J., Boo, K.J., Kim, D.H., Han, D.H., Choe, H.K., Kim, C.R., Sun, W., Kim, H., Kim, K.J., Lee, H., Metzger, E., Schuele, R., Yoo, S.H., Takahashi, J.S., Cho, S.H., Son, G.H., and Baek, S.H. (2014) Phosphorylation of LSD1 by PKCα Is Crucial for Circadian Rhythmicity and Phase Resetting. Molecular Cell 53(5), (Cover Article) 6. Baek, S.H. and Kim, K.I. (2014) Emerging Roles of Orphan Nuclear Receptors in Cancer. Annual Review of Physiol. 76(19), Lee, J.M., Lee, J.S., Kim, H.K., Kim, K.K., Park, H.J., Kim, J.-Y., Lee, S.H., Kim, I.S., Kim, J.M., Lee, M.K., Chung, C.H., Seo, S.-B., Yoon, J.-B., Ko, E.Y., Noh, D.-Y., Kim, K.I., Kim, K.K., and Baek, S.H. (2012) EZH2 Generates a Methyl Degron That Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex. Molecular Cell 48, (Cover Article)

17 8. Kim, H., Lee, J.M., Lee, G., Bhin, J., Oh, S.K., Kim, K., Pyo, K.E., Lee, J.S., Yim, H.Y., Kim, K.I., Hwang, D., Chung, J., and Baek, S.H. (2011) DNA Damage-Induced RORα is Crucial for p53 Stabilization and Increased Apoptosis. Molecular Cell 44, (Cover Article) 9. Lee, J.S., Kim, Y., Bhin, J., Shin, H-J. R., Nam, H.J., Lee, S.H., Yoon, J.-B., Binda, O., Gozani, O., Hwang, D., and Baek, S.H. (2011) Hypoxia Induced Methylation of a Pontin Chromatin Remodeling Factor. Proc. Natl. Acad. Sci. USA 108, Baek, S.H. (2011) When Signaling Kinases Meet Histone and Histone Modifiers in the Nucleus. Molecular Cell 42, Lee, J. S., Kim, Y., Kim, I.S., Kim, B., Choi, H.J., Lee, J.M., Shin, H-J. R., Kim, J.H., Kim, J.-Y., Seo, S.-B., Lee, H., Binda, O., Gozani, O., Semenza, G.L., Kim, M., Kim, K.I., Hwang, D.H., and Baek, S.H. (2010) Negative Regulation of Hypoxic Responses via Induced Reptin Methylation. Molecular Cell 39, (Cover Article) 12. Lee, J.M., Kim, I.S. Kim, H., Lee, J.S., Kim, K., Yim, H.Y., Jeong, J., Kim, J.H., Kim, J.-Y., Lee, H., Seo, S.-B., Kim, H., Rosenfeld, M.G., Kim, K.I., and Baek, S.H. (2010) RORα Attenuates Wnt/β-Catenin Signaling by PKCα-dependent Phosphorylation in Colon Cancer. Molecular Cell 37, Baek, S.H. (2008) When ATPases Pontin and Reptin Met Telomerase. Dev. Cell 14, Kim, J.H., Lee, J.M., Nam, H.J., Choi, H.J., Yang, J.W., Lee, J.S., Kim, M.H., Kim, S.-I., Chung, C.H., Kim, K.I., and Baek, S.H. (2007) SUMOylation of a Pontin Chromatin-Remodeling Complex Reveals a New Signal Integration Code in Prostate Cancer Cells. Proc. Natl. Acad. Sci. USA 104, Kim, J.H., Choi, H.J., Kim, B., Kim, M.H., Lee, J.M., Kim, I.S., Lee, M.H., Choi, S.J., Kim, K.I., Kim, S.-I., Chung, C.H., and Baek, S.H. (2006) Roles of SUMOylation of a Reptin Chromatin Remodeling Complex in Cancer Metastasis. Nature Cell Biol. 8, Zhu, P*, Baek, S.H.*, Bourk, E.M., Ohgi, K.A., Garcia-Bassets, I., Sanjo, H., Akira, S., Kotol, P.F., Glass, C.K., Rosenfeld, M.G., and Rose, D.W. (2006) Macrophage/Cancer Cell Interactions Mediate

18 Hormone Resistance Through a Conserved Nuclear Receptor Derepression Pathway. Cell 124, (*: equal contribution) 17. Baek, S.H.*, Ohgi, K.A., Nelson, C.A., Welsbie, D., Chen, C., Sawyers, C.L., Rose, D.W., and Rosenfeld, M.G.* (2006) Ligand-specific Allosteric Regulation of Coactivator Functions of Androgen Receptor in Prostate Cancer Cells. Proc. Natl. Acad. Sci. USA 103, (*: co-corresponding author) 18. Kim, J.H., Kim, B., Ling, C., Choi, H.J., Ohgi, K.A., Tran, C, Chen, C., Chung, C.H., Huber, O., Rose, D.W., Sawyers, C.L., Rosenfeld, M.G., and Baek, S.H. (2005) Transcriptional Regulation of a Metastasis Suppressor Gene by Tip60 and β-catenin Complexes. Nature 434, Baek, S.H., Kioussi, C., Briata, P., Wang, D., Nguyen, H.D., Ohgi, K.A., Glass, C.K., Wynshaw-Boris, A., Rose, D.W., and Rosenfeld, M.G. (2003) Regulated Subset of G1 Growth-Control Genes in Response to Derepression by the Wnt Pathway. Proc. Natl. Acad. Sci. USA 100, Kioussi, C*., Briata, P*., Baek, S.H. *, Rose, D.W. *, Hamblet, N S., Herman, T., Ohgi, K.A., Lin, C., Gleiberman, A., Wang, J., Brault, V., Ruiz-Lozano, P., Nguyen, H.D., Kemler, R., Glass, C.K., Wynshaw-Boris, A., and Rosenfeld, M.G. (2002) Identification of a Wnt/Dvl/β-Catenin to Pitx2 Pathway Mediating Cell-Type-Specific Proliferation during Development. Cell 111, (*: Equal contribution) 21. Baek, S.H., Ohgi, K.A., Rose, D.W., Koo, E.H., Glass, C.K., and Rosenfeld, M.G. (2002) Exchange of N-CoR Corepressor and Tip60 Coactivator Complexes Links Gene Expression by NF-κB and β-amyloid Precursor Protein. Cell : ( )

19 신희재박사과정생 [ 공동제 1 저자 ] 이력사항 1. : : bebett5@snu.ac.kr :, :, (National Junior Research Fellowship) ( ) 1. Boo, K.J., Bhin, J.H., Jeon, Y., Kim, J.M., Shin,H-J.R., Park, J.E., Kim, K.K., Kim, C.R., Jang, H.C., Kim, I.H., Kim, V.N., Hwang, D.H., Lee, H., and Baek, S.H. (2015) Pontin Functions As an Essential Coactivator for Oct4-Dependent LincRNA expression in Mouse Embryonic Stem Cells. Nature Communications 6: Lee, J.S., Kim, Y., Bhin, J.H., Shin,H-J.R., Nam, H.J., Lee, S.H., Yoon, J.-B., Binda, O., Gozani, O., Hwang, D.H.,and Baek, S.H. (2011) Hypoxia-Induced Methylation of a Pontin Chromatin Remodeling Factor. Proc. Natl. Acad. Sci. USA 108(33), Lee,J.S., Kim,Y., Kim,I.S., Kim,B., Choi,H.J., Lee,J.M., Shin,H-J.R., Kim,J.H., Kim,J.-Y., Seo,S.-B., Lee,H., Binda,O., Gozani,O., Semenza,G.L., Kim,M., Kim,K.I., Hwang,D.H.,and Baek,S.H. (2010) Negative Regulation of Hypoxic Reponses via Induced Reptin Methylation. Molecular Cell 39, : (NRF-2011-A )

20 김현경박사 [ 공동제 1 저자 ] 이력사항 1. : : hkk@snu.ac.kr :, :, : : : ( ) 2013 Sanofi (2014- )

21 1. Lee, J.M.,* Lee, J. S,*Kim, H.K.,* Kim, K.K., Park, H.J., Kim, J.Y., Kim.J,M., Chung,C.H.,, Seo,S.-B.,, Ko, E.Y., Noh, D.Y., Kim,K.I.,, Kim, K.K, and Baek, S.H, (2013) EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4E3 Ubiquitin Ligase Complex.. Molecular Cell 48, (Molecular cell cover) (Co-1st author) 2. Kim, H.K., Lee, J.M., Lee, G.N., Bhin, J.H., Oh, S.K., Kim, K.K., Pyo, K.E., Lee, J.S., Yim, H.Y., Kim, K.I., Hwang, D.H., Chung, J.K.,and Baek, S.H. (2011) DNA Damage-Induced RORa Is Crucial for p53 Stabilization and Increased Apoptosis. Molecular Cell 44(5), (Molecular cell cover) (1st author) 3. Lee, J. M., Kim, I. S. Kim, H.K., Lee, J. S., Kim, K., Yim, H. Y., Jeong, J., Kim, J.H., Kim, J.-Y., Lee, H., Seo, S.-B., Kim, H., Rosenfeld, M. G., Kim, K. I., and Baek, S. H. (2010). RORα Attenuates Wnt/β -Catenin Signaling by PKCα-dependent Phosphorylation in Colon Cancer. Molecular Cell. 37, (2nd author) 4. Choi,H.J., Lee,J.M., Kim,H.K., Nam,H.J., Shin,H.J., Kim,D.H., Ko,E.Y., Noh,D.Y., Kim,K.I., Kim,J.H.,and Baek,S.H. (2010) Bcl3-dependent Stabilization of CtBP1 is Crucial for the Inhibition of Apoptosis and Tumor Progression in Breast Cancer. Biochem. Biophys. Res. Comm. 400, (co-author) ~ : NRF-2014R1A6A3A ( )

jaeryomading review.pdf

jaeryomading review.pdf 4 5 6 7 8 9 10 11 12 13 1. S. Kim, H. Y. Jeong, S. K. Kim, S. Y. Choi and K. J. Lee, Nano Lett. 11, 5438 (2011). 2. E. Menard, K. J. Lee, D. Y. Khang, R. G. Nuzzo and J. A. Rogers, Appl. Phys. Lett. 84,