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bioRxiv · 10.64898/2026.03.09.710545

Diverse processes drive the origination and maturation of super-enhancers and super-silencers during a vast evolutionary timescale of the bicistronic gene SMIM45

Delihas, N.
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Abstract

A central question in molecular genetics concerns how transcriptional regulatory sequences and de novo genes originate and reach evolutionary fixation. In this study, we utilize the human bicistronic gene SMIM45 as a model to analyze the evolutionary trajectories of gene development. This locus comprises several functional units: three enhancers (one featuring an embedded silencer), an exonic silencer that partially overlaps an ORF, a highly conserved ancestral sequence encoding a 68-aa microprotein, and a human-specific de novo gene encoding a 107-aa protein expressed spatiotemporally in embryonic brain tissues. We identify significant disparities in formation mechanisms; for example, the NANOG hESC enhancer originated simply via two Alu insertions that constitute the regulatory element. In contrast, the exonic silencer (ATAC-STARR-seq lymphoblastoid silent region 13815), a distinct, novel type of silencer, originated by a combination of diverse mechanisms, including a "cultivator gene" process of base pair fixation consistent with the Cultivator Model proposed by Li Zhao and coworkers. Consequently, SMIM45 exemplifies novel mechanisms of regulatory element development that occurred over several hundred million years, culminating in the birth of a human-specific de novo 107-aa cistron. The properties of these super-enhancers and super-silencers suggest a complex, intricate regulation of the 107-aa protein in fetal tissues. HighlightsSMIM45, a bicistronic gene developed an array of enhancers and silencers over several hundred million years of evolution. Enhancers and silencers formed by diverse processes during very different evolutionary time frames. The silencer ATAC-STARR-seq lymphoblastoid silent region 13815 in SMIM45 appears novel, as it is composed of two distinct segments that exhibit disparate origins and developmental pathways. This intricate regulatory apparatus points to a complex regulation of the 107-aa protein gene expressed in human embryonic brain tissues.

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Delihas, N.. 2026-03-13. Diverse processes drive the origination and maturation of super-enhancers and super-silencers during a vast evolutionary timescale of the bicistronic gene SMIM45. https://doi.org/10.64898/2026.03.09.710545

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