基因损伤和转录调控新思路---大脑在学习和年龄相关损害中都伴随着DNA破坏

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https://newsoffice.mit.edu/2015/ ... related-damage-0604
3 ^* |* C3 P4 }8 \. [9 WDNA breakage underlies both learning, age-related damage
7 F2 k' g5 `% u6 V- n) ]Process that allows brains to learn and remember also leads to degeneration with age.
$ h/ |' o/ u& H0 z% n: m( _Helen Knight | MIT News correspondent
! V0 l* W  V  y, x& N7 f6 IJune 4, 2015
& x, b# h2 F! ~Press Inquiries1 s; X0 `2 p+ t: e. w3 h, n4 F; q
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! g2 a- [) M7 t: Z& ?2 |The process that allows our brains to learn and generate new memories also leads to degeneration as we age, according to a new study by researchers at MIT.9 S0 i8 ~) c3 b4 K8 q: z) M. G$ [
The finding, reported in a paper published today in the journal Cell, could ultimately help researchers develop new approaches to preventing cognitive decline in disorders such as Alzheimer’s disease.
8 w, N$ v7 _& {8 W+ F+ u+ R0 }Each time we learn something new, our brain cells break their DNA, creating damage that the neurons must immediately repair, according to Li-Huei Tsai, the Picower Professor of Neuroscience and director of the Picower Institute for Learning and Memory at MIT.3 G3 n- z8 p, J0 m# |
This process is essential to learning and memory. “Cells physiologically break their DNA to allow certain important genes to be expressed,” Tsai says. “In the case of neurons, they need to break their DNA to enable the expression of early response genes, which ultimately pave the way for the transcriptional program that supports learning and memory, and many other behaviors.”
; E0 N' I. u. ^' ~( f9 `Slower DNA repair4 M) C6 l5 i/ d$ K
However, as we age, our cells’ ability to repair this DNA damage weakens, leading to degeneration, Tsai says. “When we are young, our brains create DNA breaks as we learn new things, but our cells are absolutely on top of this and can quickly repair the damage to maintain the functionality of the system,” Tsai says. “But during aging, and particularly with some genetic conditions, the efficiency of the DNA repair system is compromised, leading to the accumulation of damage, and in our view this could be very detrimental.”0 c; }, R( l6 ~
In previous research into Alzheimer’s disease in mice, the researchers found that even in the presymptomatic phase of the disorder, neurons in the hippocampal region of the brain contain a large number of DNA lesions, known as double strand breaks.
1 @' C- D+ U% b4 d3 v, [To determine how and why these double strand breaks are generated, and what genes are affected by them, the researchers began to investigate what would happen if they created such damage in neurons. They applied a toxic agent to the neurons known to induce double strand breaks, and then harvested the RNA from the cells for sequencing.
% W. V2 o- n% a' |+ P' a  K7 G" GThey discovered that of the 700 genes that showed changes as a result of this damage, the vast majority had reduced expression levels, as expected. Surprisingly though, 12 genes — known to be those that respond rapidly to neuronal stimulation, such as a new sensory experience — showed increased expression levels following the double strand breaks.
/ ^' k; W1 i6 b! T7 @To determine whether these breaks occur naturally during neuronal stimulation, the researchers then treated the neurons with a substance that causes synapses to strengthen in a similar way to exposure to a new experience.
8 d9 Q/ b, W. W“Sure enough, we found that the treatment very rapidly increased the expression of those early response genes, but it also caused DNA double strand breaks,” Tsai says.; S# {% t' t) d& k8 R2 F4 a
The good with the bad! ?4 d+ u; V7 s; d3 M
In further studies the researchers were able to confirm that an enzyme known as topoisomerase IIβ is responsible for the DNA breaks in response to stimulation, according to the paper’s lead author Ram Madabhushi, a postdoc in Tsai’s laboratory.
2 y8 g, O/ B2 t“When we knocked down this enzyme, we found that both double strand break formation and the expression of early response genes was reduced,” Madabhushi says.% i; S+ F" ^; |( O/ ^( e
Finally, the researchers attempted to determine why the genes need such a drastic mechanism to allow them to be expressed. Using computational analysis, they studied the DNA sequences near these genes and discovered that they were enriched with a motif, or sequence pattern, for binding to a protein called CTCF. This “architectural” protein is known to create loops or bends in DNA.
1 J& ]( O% P  X" |& u. y' GIn the early-response genes, the bends created by this protein act as a barrier that prevents different elements of DNA from interacting with each other — a crucial step in the genes’ expression.
; Z( y7 w* C+ F  D1 Q4 |The double strand breaks created by the cells allow them to collapse this barrier, and enable the early response genes to be expressed, Tsai says.6 n) ?  Z/ \  N, ^; n
“Surprisingly then, even though conventional wisdom dictates that DNA lesions are very bad — as this ‘damage’ can be mutagenic and sometimes lead to cancer — it turns out that these breaks are part of the physiological function of the cell,” Tsai says.! c& l( H0 u  l
Previous research has shown that the expression of genes involved in learning and memory is reduced as people age. So the researchers now plan to carry out further studies to determine how the DNA repair system is altered with age, and how this compromises the ability of cells to cope with the continued production and repair of double strand breaks.+ K" w- Q0 t1 X
They also plan to investigate whether certain chemicals could enhance this DNA repair capacity.. N& \% {7 K& S. y
The paper represents an important conceptual advance in our understanding of gene regulation, according to Bruce Yankner, a professor of genetics and neurology at Harvard Medical School who was not involved in the research.
4 j; `( H: u. S% N. i( E“The work elegantly links DNA strand break formation by the enzyme topoisomerase IIβ to the temporal control of transcription, providing the most compelling evidence to date that this is a core transcriptional control mechanism,” he says.  “I anticipate that this advance will have broad implications ranging from the basic biology of transcription to pathological mechanisms involved in diseases such as Alzheimer’s disease.”
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. Y6 G8 H. _$ x3 o" m6 c- K大脑在学习和年龄相关损害中都伴随着DNA破坏0 {4 E8 Q# [, M1 a' L6 l0 J

8 k. K1 ]) M3 A麻省理工学院的一项新的研究发现，我们的大脑学习和产生新记忆的过程会随着年老退化。这一发现发表在近期的Cell杂志上，可能帮助研究人员开发新的方法用于防止阿兹海默等疾病中出现的认知能力下降。 # _! y, _! ]. D/ P: M& R" t; _: ]

5 @# m% O* K2 @$ a" n* O& ULi-Huei Tsai, the Picower Professor of Neuroscience and director of the Picower Institute for Learning and Memory at MIT 表示每当我们学习新东西时，我们的脑细胞会破坏他们的DNA，产生损伤。神经元必须立即修复这些损伤。这是学习和记忆时必不可少的过程。他说：“生理情况下（不是病理情况下）细胞会破坏他们的DNA，使某些重要基因被表达。神经元需要破坏DNA，使早期反应基因能够表达，这为转录编程做好准备以支持学习，记忆以及许多其他行为。”（类似于IPS的重编程过程？产生大量的DNA损伤？）
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较慢的DNA修复 * j2 J, g2 b) V5 a7 ^. p. B7 S
然而，随着年龄的增长，我们细胞修复这种DNA损伤的能力逐渐减弱，导致功能退化。Tsai说。 “当我们年轻的时候，学习新的东西时大脑产生DNA损伤，但我们的细胞可以应付这种局面，能迅速修复损伤，保持系统的功能。但是，随着机体的老化，特别是在某些遗传背景下，DNA修复的效率受到损害，从而导致损伤的积累，在我们看来这是很不利的。”
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在之前使用小鼠进行阿茨海默症的研究中，研究人员发现，即使是在疾病的出现症状前，大脑的海马区神经元中就已经含有大量DNA损伤（双链断裂）。 为了确定这些双链断裂产生的原因和过程以及受其影响的基因，研究人员设计了一系列的实验调查如果人为地在神经元上制造这样的损伤，会发生什么呢。他们使用一种毒性剂刺激神经元，已知它可以诱导双链断裂，然后从细胞中收集RNA用于测序分析。（问题是药物作用和自然状况下的损伤是一样的吗？）7 m$ J2 v+ {  c4 t
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他们发现这些损伤影响大约700个基因，绝大多数的基因的表达水平降低，这符合预期。令人惊讶的是，有12个基因（它们是已知的对神经元刺激比如新的感官体验响应迅速的基因，早期反应基因）的表达水平提高了。- W' N$ }2 j% k% M% z7 w5 `

! ?% Z" M" D1 n. {为了确定神经元在刺激下本身是否产生这些损伤，研究人员随后使用一种药物（突触发生强化，效果类似神经元受到刺激时所发生的）处理神经元。Tsai说：“结果很明确，药物处理很快提高了那些早期反应基因的表达，同时，造成了DNA双链断裂。”
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好中有坏
% J& d; M: n' V  Y( ]Ram Madabhushi, a postdoc in Tsai’s laboratory 表示在进一步的研究中，他们确定一种叫做 topoisomerase IIβ 的酶主导了神经元在刺激后产生的DNA损伤。他说：“当我们把这种酶从细胞中去除后（敲除），我们发现，DNA双链断裂和早期应答基因的表达都减少了。”最后，研究者试图确定为什么这些基因需要使用这样一种剧烈的机制来提高它们的表达。（为什么早期反应基因的表达需要伴随着DNA损伤，欲练此功必先自宫吗？）。他们使用计算分析研究了这些基因附近的DNA序列，发现它们富含某些基序（motif），这些基序可以结合到一个被称为CTCF的蛋白上。这个蛋白质像个建筑师可以让DNA形成环形或弯曲结构。这些蛋白质在早期反应基因周围产生的弯曲是一个屏障，可以防止DNA之间的彼此交互（DNA之间的交互作用是基因表达的关键步骤）。细胞产生的双链断裂让这些障碍崩溃，从而启动早期反应基因的表达。
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Tsai说：“这个发现是非常出乎意料的，依照常理来说DNA断裂损伤是非常糟糕的，因为这些损伤会导致突变，甚至癌化。但是事实证明，这些断裂是细胞的生理功能的一部分。”
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( r% O& y2 ~  g1 f# {* K& w以前的研究表明，学习和记忆相关的基因的表达会随着年龄的增加而降低。因此，研究人员计划开展进一步的研究，以确定DNA修复系统为什么会随着年龄的增长而减弱，以及细胞是如何平衡持续产生的双链断裂和修复的。他们还计划研究是否可以寻找某些化学物质用于加强DNA的修复能力。
2 S, H. f7 G% d) G. t3 k6 }Bruce Yankner, a professor of genetics and neurology at Harvard Medical School（并没有参与此项研究）表示这个发现让我们对基因调控有了进一步的了解。他说：“这项工作将 topoisomerase IIβ 引起的DNA断裂和瞬时的基因转录调控相结合。使用迄今为止最有力的证据证明了这是一个核心的转录调控机制。 我预计，这将具有广泛的影响，从基础生物学中的转录调控研究，到疾病机理的研究，比如阿茨海默症。”
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) r4 s* u7 Z4 C+ ]+ V, S- x非常有意思的一个研究，希望大家喜欢。, \; w, q5 N9 y- m

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