Dissecting the contribution of transposable elements to interphase chromosome structure

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BACKGROUND: Transposable elements (TEs) occupy nearly half of the human genome and play diverse biological roles. Despite their abundance, the extent to which TEs contribute to three-dimensional (3D) genome structure remains unclear. RESULTS: To investigate this, we generate a modified Hi-C analysis pipeline to probe TE-associated chromatin interactions. Our analysis reveals that TE sequences are responsible for 3D genome structure in interphase nuclei. This phenomenon is mediated by the recruitment of specific epigenetic/transcription factors to TEs, which both promote and impair chromatin contacts. We computationally identified known factors positively associated with chromatin contacts (CTCF, RAD21, SMC3) and chromatin contact impairing proteins (RNF2). Additionally, we identiy potential novel factors (SMARCA4, MAFK), which, when knocked down, lead to decreased chromatin contacts and loops at and between TEs. Notably, SMARCA4 knockdown selectively reduce short-range contacts, highlighting its role in maintaining 3D genome structure through TE binding. CONCLUSIONS: Overall, our findings demonstrate that TEs are crucial determinants of 3D genome organization in mammalian cells.

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