Dekker Job
Program in Gene Function and Expression and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Plantation Street, Worcester, MA 01605-4321, USA.
Genome Biol. 2007;8(6):R116. doi: 10.1186/gb-2007-8-6-r116.
Base-composition varies throughout the genome and is related to organization of chromosomes in distinct domains (isochores). Isochore domains differ in gene expression levels, replication timing, levels of meiotic recombination and chromatin structure. The molecular basis for these differences is poorly understood.
We have compared GC- and AT-rich isochores of yeast with respect to chromatin conformation, histone modification status and transcription. Using 3C analysis we show that, along chromosome III, GC-rich isochores have a chromatin structure that is characterized by lower chromatin interaction frequencies compared to AT-rich isochores, which may point to a more extended chromatin conformation. In addition, we find that throughout the genome, GC-rich and AT-rich genes display distinct levels of histone modifications. Interestingly, elimination of the histone deacetylase Rpd3p differentially affects conformation of GC- and AT-rich domains. Further, deletion of RPD3 activates expression of GC-rich genes more strongly than AT-rich genes. Analyses of effects of the histone deacetylase inhibitor trichostatin A, global patterns of Rpd3p binding and effects of deletion of RPD3 on histone H4 acetylation confirmed that conformation and activity of GC-rich chromatin are more sensitive to Rpd3p-mediated deacetylation than AT-rich chromatin.
We find that GC-rich and AT-rich chromatin domains display distinct chromatin conformations and are marked by distinct patterns of histone modifications. We identified the histone deacetylase Rpd3p as an attenuator of these base composition-dependent differences in chromatin status. We propose that GC-rich chromatin domains tend to occur in a more active conformation and that Rpd3p activity represses this propensity throughout the genome.
基因组中碱基组成各异，且与染色体在不同结构域（等密度区）中的组织方式相关。等密度区在基因表达水平、复制时间、减数分裂重组水平和染色质结构方面存在差异。这些差异的分子基础尚不清楚。
我们比较了酵母中富含GC和富含AT的等密度区在染色质构象、组蛋白修饰状态和转录方面的情况。使用3C分析，我们发现沿着第三条染色体，与富含AT的等密度区相比，富含GC的等密度区具有一种染色质结构，其特征是染色质相互作用频率较低，这可能表明染色质构象更为伸展。此外，我们发现，在整个基因组中，富含GC和富含AT的基因显示出不同水平的组蛋白修饰。有趣的是，组蛋白去乙酰化酶Rpd3p的缺失对富含GC和富含AT的结构域的构象有不同影响。此外，RPD3的缺失对富含GC的基因的激活作用比对富含AT的基因更强。对组蛋白去乙酰化酶抑制剂曲古抑菌素A的作用、Rpd3p结合的全局模式以及RPD3缺失对组蛋白H4乙酰化的影响进行分析，证实了富含GC的染色质的构象和活性比富含AT的染色质对Rpd3p介导的去乙酰化更敏感。
我们发现富含GC和富含AT的染色质结构域具有不同的染色质构象，并以不同的组蛋白修饰模式为特征。我们确定组蛋白去乙酰化酶Rpd3p是染色质状态中这些碱基组成依赖性差异的衰减因子。我们提出，富含GC的染色质结构域倾向于以更活跃的构象出现，并且Rpd3p的活性在整个基因组中抑制这种倾向。
