Frenette Béatrice, Guéno Josselin, Houde Nicolas, Landry-Truchon Kim, Giguère Anthony, Ashok Theyjasvi, Ryckman Abigail, Morton Brian R, Mansfield Jennifer H, Jeannotte Lucie
Centre de Recherche sur le Cancer de L'Université Laval, Centre de Recherche du CHU de Québec-Université Laval (Oncology), 1401, 18e Rue, Québec, QC, G1J 1Z4, Canada.
Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, Canada.
Sci Rep. 2024 Dec 28;14(1):30903. doi: 10.1038/s41598-024-81867-0.
Hoxa5 plays numerous roles in development, but its downstream molecular effects are mostly unknown. We applied bulk RNA-seq assays to characterize the transcriptional impact of the loss of Hoxa5 gene function in seven different biological contexts, including developing respiratory and musculoskeletal tissues that present phenotypes in Hoxa5 mouse mutants. This global analysis revealed few common transcriptional changes, suggesting that HOXA5 acts mainly via the regulation of context-specific effectors. However, Hox genes themselves appeared as potentially conserved targets of HOXA5 across tissues. Notably, a trend toward reduced expression of HoxA genes was observed in Hoxa5 null mutants in several tissue contexts. Comparative analysis of epigenetic marks along the HoxA cluster in lung tissue from two different Hoxa5 mutant mouse lines revealed limited effect of either mutation indicating that Hoxa5 gene targeting did not significantly perturb the chromatin landscape of the surrounding HoxA cluster. Combined with the shared impact of the two Hoxa5 mutant alleles on phenotype and Hox expression, these data argue against the contribution of local cis effects to Hoxa5 mutant phenotypes and support the notion that the HOXA5 protein acts in trans in the control of Hox gene expression.
Hoxa5在发育过程中发挥着多种作用，但其下游分子效应大多未知。我们应用批量RNA测序分析来表征Hoxa5基因功能缺失在七种不同生物学背景下的转录影响，包括发育中的呼吸和肌肉骨骼组织，这些组织在Hoxa5小鼠突变体中呈现出表型。这项全局分析揭示了很少有共同的转录变化，这表明HOXA5主要通过调控特定背景下的效应因子发挥作用。然而，Hox基因本身似乎是HOXA5在不同组织中的潜在保守靶点。值得注意的是，在几种组织背景下的Hoxa5基因敲除突变体中观察到HoxA基因表达降低的趋势。对来自两种不同Hoxa5突变小鼠品系的肺组织中HoxA基因簇的表观遗传标记进行比较分析，发现两种突变的影响都有限，这表明靶向Hoxa5基因并没有显著扰乱周围HoxA基因簇的染色质景观。结合两个Hoxa5突变等位基因对表型和Hox表达的共同影响，这些数据反对局部顺式效应对Hoxa5突变体表型的贡献，并支持HOXA5蛋白以反式作用调控Hox基因表达的观点。
