Expanding housekeeping gene concepts: The role of retroelements in gene expression stability across tissues
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Background Housekeeping genes (HKGs), essential for cellular differentiation, are traditionally thought to be uniformly expressed. However, recent analyses revealed variable expression of most genes across tissues, challenging this view. Identifying HKGs based on stable expression necessitates precise, repeated experiments. The limited number of transcription factors during differentiation implies that HKGs stabilise phenotypes through compensatory gene regulation. Methods We investigated the influence of retroelements, which constitute approximately 40% of the human genome, on gene expression stability based on proximity to transcriptional start sites (TSSs). By mapping CpG islands and retroelements within 10 kb of TSSs, we analysed 56 RNA sequencing datasets. Results CpG-island genes near Alu elements exhibited low expression variability, especially when the Alu elements were closer to the TSSs. Conversely, non-CpG island genes near L1 and LTR elements showed high variability, indicating distinct regulatory roles. Despite the constant number of Alu-adjacent CpG-island genes across tissues, their expression was the strongest in embryonic stem cells and declined in most differentiated tissues, except for an increase in the ovary and testis. Conclusions Alu elements near CpG islands help stabilise phenotypes through compensatory downregulation of HKGs. These findings support the expansion of the HKG concept to include genes maintaining stable phenotypes during tissue differentiation, aiding in differentiation stage identification.