The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain.
The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain.
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DOI：
10.1093/nar/gkac1188
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发表时间：
2023-01-25
影响因子：
14.9
通讯作者：
Liefke, Robert
中科院分区：
文献类型：
--
作者：
Weber, Lisa Marie;Jia, Yulin;Stielow, Bastian;Gisselbrecht, Stephen S.;Cao, Yinghua;Ren, Yanpeng;Rohner, Iris;King, Jessica;Rothman, Elisabeth;Fischer, Sabrina;Simon, Clara;Forne, Ignasi;Nist, Andrea;Stiewe, Thorsten;Bulyk, Martha L.;Wang, Zhanxin;Liefke, Robert
赖氨酸乙酰转移酶KAT 6A（MOZ，MYST 3）属于MYST家族的染色质调节剂，促进组蛋白乙酰化。KAT 6A的失调与发育综合征和急性髓性白血病（AML）的发病有关。以前的工作表明，KAT 6A是通过组蛋白结合PHD指，转录因子和染色质结合相互作用伴侣的组合功能招募到其基因组靶标。在这里，我们证明了一个翼螺旋（WH）结构域在非常N-末端的KAT 6A特异性相互作用与未甲基化的CpG基序。这种DNA结合功能导致KAT 6A与非甲基化CpG岛（CGI）全基因组相关。DNA结合必需氨基酸的突变完全消除了KAT 6A在CGI处的富集。相反，第二WH结构域或组蛋白尾结合PHD指的缺失仅微妙地影响KAT 6A与CGI的结合。KAT 6A WH 1突变体的过表达对H3 K9组蛋白乙酰化具有显性负效应，这与KAT 6A HAT结构域突变体过表达的效应相当。综上所述，我们的工作揭示了KAT 6A以前未被认识的染色质募集机制，为KAT 6A在基因调控和人类疾病中的作用提供了新的视角。
The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases.
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影响因子：
14.9
作者：
Dreveny I;Deeves SE;Fulton J;Yue B;Messmer M;Bhattacharya A;Collins HM;Heery DM
通讯作者：
Heery DM
影响因子：
7.7
作者：
Farcas AM;Blackledge NP;Sudbery I;Long HK;McGouran JF;Rose NR;Lee S;Sims D;Cerase A;Sheahan TW;Koseki H;Brockdorff N;Ponting CP;Kessler BM;Klose RJ
通讯作者：
Klose RJ
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
10.5
作者：
Katsumoto, Takuo;Aikawa, Yukiko;Kitabayashi, Issay
通讯作者：
Kitabayashi, Issay
影响因子：
46.9
作者：
Berger, Michael F.;Philippakis, Anthony A.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.