Counterregulation of chromatin deacetylation and histone deacetylase occupancy at the integrated promoter of human immunodeficiency virus type 1 (HIV-1) by the HIV-1 repressor YY1 and HIV-1 activator Tat
Counterregulation of chromatin deacetylation and histone deacetylase occupancy at the integrated promoter of human immunodeficiency virus type 1 (HIV-1) by the HIV-1 repressor YY1 and HIV-1 activator Tat
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DOI：
10.1128/mcb.22.9.2965-2973.2002
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发表时间：
2002-05-01
影响因子：
5.3
通讯作者：
Margolis, DM
中科院分区：
文献类型：
--
作者：
He, GC;Margolis, DM
人类免疫缺陷病毒1型（HIV-1）转录的抑制可能有助于感染的CD 4（+）细胞中前病毒静止期的建立或维持。宿主因子YY 1和LSF协同将组蛋白脱乙酰基酶1（HDAC 1）募集到HIV-1长末端重复序列（LTR）并抑制转录。我们在这里展示了HDAC 1在整合的LTR的转录起始位点附近的定位核小体（nuc 1）的占据调节。我们发现YY 1的表达增加了HDAC 1的占据，减少了nuc 1的乙酰化，并下调了LTR的表达。当Wt过表达抑制达特活化时，HDAC 1募集和组蛋白低乙酰化也被观察到。没有HDAC 1相互作用结构域并且不能抑制LTR激活的YY 1突变体不能将HDAC 1募集到LTR或降低nuc 1乙酰化。此外，抑制LSF占据和LTR阻遏的LSF的显性负突变体（dnLSF）的表达导致乙酰化和nuc 1处的HDAC 1占据降低。相反，将细胞暴露于组蛋白去乙酰化酶抑制剂利司他汀A或通过HIV-1达特激活LTR表达导致HDAC 1从nuc 1置换，与组蛋白H4的乙酰化增加相关。HDAC 1向LTR nuc 1的募集可以抵消达特激活并抑制LTR表达。值得注意的是，当抑制被克服时，LTR激活与HDACI占用减少相关。由于尽管有效抑制病毒复制，但整合的HIV-1基因组的持续存在是当前抗逆转录病毒治疗的主要障碍，因此选择性破坏染色体前病毒静止的策略可能在未来的艾滋病治疗中发挥作用。
Repression of human immunodeficiency virus type 1 (HIV-1) transcription may contribute to the establishment or maintenance of proviral quiescence in infected CD4(+) cells. The host factors YY1 and LSF cooperatively recruit histone deacetylase 1 (HDAC1) to the HIV-1 long terminal repeat (LTR) and inhibit transcription. We demonstrate here regulation of occupancy of HDAC1 at a positioned nucleosome (nuc 1) near the transcription start site of integrated LTR. We find that expression of YY1 increases occupancy by HDAC1, decreases acetylation at nuc 1, and downregulates LTR expression. HDAC1 recruitment and histone hypoacetylation were also seen when Tat activation was inhibited by the overexpression of Wt. A YY1 mutant without an HDAC1 interaction domain and incompetent to inhibit LTR activation fails to recruit HDAC1 to LTR or decrease nuc 1 acetylation. Further, expression of a dominant-negative mutant of LSF (dnLSF), which inhibits LSF occupancy and LTR repression, results in acetylation and decreased HDAC1 occupancy at nuc 1. Conversely, exposure of cells to the histone deacetylase inhibitor trichostatin A or activation of LTR expression by HIV-1 Tat results in the displacement of HDAC1 from nuc 1, in association with increased acetylation of histone H4. Recruitment of HDAC1 to the LTR nuc 1 can counteract Tat activation and repress LTR expression. Significantly, when repression is overcome, LTR activation is associated with decreased HDACI occupancy. Since the persistence of integrated HIV-1 genomes despite potent suppression of viral replication is a major obstacle for current antiretroviral therapy, strategies to selectively disrupt the quiescence of chromosomal provirus may play a role in the future treatment of AIDS.