Mannion Brandon J, Tran Stella, Plajzer-Frick Ingrid, Novak Catherine S, Afzal Veena, Akiyama Jennifer A, Sospedra-Arrufat Ismael, Barton Sarah, Beckman Erik, Garvin Tyler H, Godfrey Patrick, Godoy Janeth, Hunter Riana D, Kato Momoe, Kosicki Michael, Kronshage Anne N, Lee Elizabeth A, Meky Eman M, Pham Quan T, von Maydell Kianna, Zhu Yiwen, Lopez-Rios Javier, Dickel Diane E, Osterwalder Marco, Visel Axel, Pennacchio Len A
Environmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA, USA.
Comparative Biochemistry Program, University of California, Berkeley, CA, USA.
Nat Commun. 2025 Aug 8;16(1):7313. doi: 10.1038/s41467-025-62497-0.
Chromatin signatures are widely used to identify tissue-specific in vivo enhancers, but their sensitivity and specificity remains unclear. Here we show that many developmental enhancers remain undetectable using currently available chromatin data. In an initial comparison of over 1200 developmental enhancers with tissue-matched chromatin data, 14% (n = 285) lacked canonical enhancer-associated chromatin signatures. To further assess the prevalence of enhancers missed by chromatin profiling approaches, we used a high-throughput transgenic enhancer assay to screen the regulatory landscapes of two key developmental genes at 5 kb resolution, spanning 1.3 Mb of mouse sequence in total. We observed that 23 of 88 (26%) in vivo enhancers discovered by this approach lacked enhancer-associated chromatin signatures in the respective tissue. Our findings suggest the existence of tens of thousands of enhancers that remain undiscovered by currently available chromatin data, underscoring the continued need for expanding resources for enhancer discovery.
染色质特征被广泛用于识别体内组织特异性增强子，但其敏感性和特异性仍不明确。在这里，我们表明，使用目前可用的染色质数据，许多发育增强子仍然无法检测到。在对1200多个发育增强子与组织匹配的染色质数据进行的初步比较中，14%（n = 285）缺乏典型的增强子相关染色质特征。为了进一步评估染色质分析方法遗漏的增强子的普遍性，我们使用高通量转基因增强子检测法，以5 kb的分辨率筛选两个关键发育基因的调控图谱，总共跨越1.3 Mb的小鼠序列。我们观察到，通过这种方法发现的88个体内增强子中有23个（26%）在各自的组织中缺乏增强子相关染色质特征。我们的研究结果表明，目前可用的染色质数据仍未发现数以万计的增强子，这突出了继续需要扩大增强子发现资源的必要性。
