Pseudogenes have historically been regarded as nonfunctional remnants of genome evolution. However, relative to other noncoding genomic elements, their promoter architecture and epigenetic regulation remain incompletely understood. Here, we systematically characterize pseudogene promoters and compare them with those of protein-coding genes and long noncoding RNAs. To do this, we integrate matched transcriptomic and epigenomic data across 26 human tissues from the EN-TEx (ENCODE-GTEx) project. We uniformly annotate promoters with chromatin features (histone modifications, chromatin accessibility, and DNA methylation), sequence motifs, and evolutionary conservation, generating an online catalog. Leveraging this catalog, we show that, across multiple tissues, transcribed, unprocessed pseudogenes exhibit chromatin patterns similar to those of active protein-coding genes. In contrast, transcribed, processed pseudogenes show a different pattern: most lack the canonical hallmarks of transcription (e.g., active histone marks) at their promoters. Instead, their promoters show increased overlap with LINE elements, enrichment for YY1-like binding motifs, and higher Hi-C contact frequency, particularly with distal enhancer-like regulatory regions. Together with their greater conservation (relative to unprocessed pseudogenes), these features suggest that the transcription of processed pseudogenes may require regulatory mechanisms distinct from canonical promoter-associated epigenetic activation.

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