Regional specification is critical for skin development, regeneration, and evolution. The contribution of epigenetics in this process remains unknown. Here, using avian epidermis, we find two major strategies regulate β-keratin gene clusters. (1) Over the body, macro-regional specificities (scales, feathers, claws, etc.) established by typical enhancers control five subclusters located within the epidermal differentiation complex on chromosome 25; (2) within a feather, micro-regional specificities are orchestrated by temporospatial chromatin looping of the feather β-keratin gene cluster on chromosome 27. Analyses suggest a three-factor model for regional specification: competence factors (e.g., AP1) make chromatin accessible, regional specifiers (e.g., Zic1) target specific genome regions, and chromatin regulators (e.g., CTCF and SATBs) establish looping configurations. Gene perturbations disrupt morphogenesis and histo-differentiation. This chicken skin paradigm advances our understanding of how regulation of big gene clusters can set up a two-dimensional body surface map.

区域规格对于皮肤的发育，再生和进化至关重要。表观遗传学在这一过程中的贡献仍然未知。在这里，我们利用鸟类表皮发现了两种主要的调节β-角蛋白基因簇的策略。（1）在身体上，由典型增强子建立的宏观区域特异性（鳞片，羽毛，爪子等）控制着位于25号染色体上表皮分化复合体内的五个亚群；（2）在羽毛中，微区的特异性是由27号染色体上的羽毛β-角蛋白基因簇的颞染色质环所编排的。分析表明，区域规范的三因素模型是：能力因素（例如AP1）使染色质可及，区域说明符（例如Zic1）针对特定的基因组区域，以及染色质调节剂（例如 CTCF和SATB）建立循环配置。基因扰动会破坏形态发生和组织分化。这种鸡皮范例提高了我们对大基因簇调控如何建立二维人体表面图的理解。