생명과학회지 (Journal of Life Science)

  • 제29권9호
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  • Pages.1002-1009
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  • 2019
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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생애 초기 유해 경험이 우울증의 발병과 p11 유전자의 후성유전기전에 미치는 영향

Effects of Early Life Stress on the Development of Depression and Epigenetic Mechanisms of p11 Gene

  • 서미경 (인제대학교 백인제기념임상의학연구소) ;
  • 최아정 (인제대학교 백인제기념임상의학연구소) ;
  • 이정구 (인제대학교 백인제기념임상의학연구소) ;
  • 엄상화 (인제대학교 의과대학 예방의학교실) ;
  • 박성우 (인제대학교 백인제기념임상의학연구소) ;
  • 석대현 (인제대학교 의과대학 생화학교실)
  • Seo, Mi Kyoung (Paik Institute for Clinical Research, Inje University) ;
  • Choi, Ah Jeong (Paik Institute for Clinical Research, Inje University) ;
  • Lee, Jung Goo (Paik Institute for Clinical Research, Inje University) ;
  • Urm, Sang-Hwa (Department of Preventive Medicine, College of Medicine, Inje University) ;
  • Park, Sung Woo (Paik Institute for Clinical Research, Inje University) ;
  • Seog, Dae-Hyun (Department of Biochemistry, College of Medicine, Inje University)
  • 투고 : 2019.04.02
  • 심사 : 2019.04.22
  • 발행 : 2019.09.30
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초록

생애 초기 유해 경험은 우울증의 위험성을 높이며, 성인기 스트레스의 민감성에 영향을 미칠 수 있다. 출생 후 모성 분리(MS)로 인한 성인기 스트레스(장기간 예측 불가능한 스트레스; CUS)의 취약성에 p11 유전자의 후성유전기전이 영향을 미치는 지를 확인하였다. 출생 직후부터 21일 동안 하루 3시간 동안 새끼 생쥐를 어미 생쥐로부터 분리시켜 새끼 생쥐가 성체가 되었을 때 CUS를 3주 동안 매일 적용하였다. Real time PCR기법으로 해마의 p11 발현 양을 측정하였고, 염색질 면역 침전 분석법으로 p11 promoter의 히스톤 H3 아세틸화 및 메틸화 양을 측정하였다. 강제수영검사에서 우울 유사 행동을 측정하였다. MS군 및 CUS군은 p11 mRNA 발현 양을 유의하게 감소시켰으며, MS+CUS군은 CUS군에 비해 p11 발현 양을 유의하게 증가시켰다. 또한 MS+CUS군은 CUS군에 비해 H3 아세틸화를 감소시켰다. 이러한 감소는 HDAC5 mRNA 발현 증가와 일치하였다. MS+CUS군은 CUS군에 비해 H3K4 메틸화를 감소시켰으며, H3K27 메틸화를 증가시켰다. 강제수영검사에서 p11 발현이 가장 많이 감소된 MS+CUS군이 대조군에 비해 더 긴 부동 시간을 나타내었다. 출생 후 모성 분리를 경험하고 성체 기간에 스트레스를 함께 받은 생쥐는 성체기간에만 스트레스를 받은 생쥐보다 훨씬 더 큰 후성유전 변화를 보여주었다. 생애 초기 유해 경험은 해마에서 p11 유전자의 히스톤 변형을 통해 성체 스트레스 효과를 더 악화시키는 것으로 생각된다.

Early life stress (ELS) increases the risk of depression. ELS may be involved in the susceptibility to subsequent stress exposure during adulthood. We investigated whether epigenetic mechanisms of p11 promoter affect the vulnerability to chronic unpredictable stress (CUS) induced by the maternal separation (MS). Mice pups were separated from their dams (3 hr/day from P1-P21). When the pups reached adulthood, we applied CUS (daily for 3 weeks). The levels of hippocampal p11 expression were analyzed by quantitative real-time PCR. The levels of acetylated and methylated histone H3 at p11 promoter were measured by chromatin immunoprecipitation. Depression-like behavior was measured by the forced swimming test (FST). The MS and CUS group exhibited significant decreases in p11 mRNA level and the MS plus CUS group had a greater reduction in this level than the CUS group. The MS plus CUS group also resulted in greater reduction in H3 acetylation than the CUS group. This reduction was associated with an upregulation of histone deacetylase 5. Additionally, the MS plus CUS group showed a greater decrease in H3K4met3 level and a greater increase in H3K27 met3 level than the CUS group. Consistent with the reduction of p11 expression, the MS plus CUS group displayed longer immobility times in the FST compared to the control group. Mice exposed to MS followed by CUS had much greater epigenetic alterations in the hippocampus compared to adult mice that only experienced CUS. ELS can exacerbate the effect of stress exposure during adulthood through histone modification of p11 gene.

키워드

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