Early inhibition of METTL3 mirrors SEC disruption during reprogramming, lowering Klf4 and Myc expression and cutting reprogramming efficiency, while inhibiting METTL3 at mid-to-late stages can boost colony formation, indicating stage-specific roles for m6A in reprogramming.

SEC functions as a master switch that actively drives cell identity changes by coordinating transcription elongation and RNA modification throughout reprogramming and differentiation.

SEC inhibition causes polymerase pausing and reduces Ser2 phosphorylation at Klf4 and Myc promoters, accompanied by a global drop in nascent RNA synthesis; conversely, overexpressing the SEC component ELL increases nascent transcription.

During retinoic acid-induced differentiation, SEC inhibition selectively impairs neural lineage differentiation, with decreased m6A and stalled transcription at neural genes Nes and Tubb3, signaling lineage-specific roles for SEC and m6A.

The findings bear on development, tissue regeneration, and cancer, as SEC's role as a METTL3 scaffold links transcription elongation to the epitranscriptome, highlighting potential therapeutic targets for diseases involving improper cell identity.

Overall, SEC-mediated m6A deposition at specific loci coordinates pause-release and transcriptional activation during cell fate transitions, revealing a coordinated transcriptional-epitranscriptomic mechanism.

A novel finding shows over 40% of SEC target transcripts carry m6A marks; SEC inhibition lowers global m6A and reduces specific m6A sites on Klf4 and Myc, suggesting a co-transcriptional role for SEC in depositing m6A via interaction with METTL3.

Disrupting SEC with KL-2 severely impairs reprogramming of mouse embryonic fibroblasts to iPSCs and neuroectoderm differentiation of embryonic stem cells, without compromising cell survival under steady-state conditions.

SEC and METTL3 operate in a single pathway for pause release and m6A deposition; METTL3 overexpression cannot rescue SEC disruption, and combined inhibition yields no extra effect on polymerase pausing.

SEC modulates RNA polymerase II pausing and release at target genes; early-activated genes such as Klf4 and Myc show promoter-proximal pausing that is rapidly released during reprogramming, whereas OCT4 and SOX2 exhibit different timing.

BRD4 may drive mesendoderm differentiation, while SEC supports neural lineage, suggesting molecular determinants of lineage choice between elongation mechanisms.

Early SEC inhibition collapses reprogramming efficiency by keeping cells in a mesenchymal state and reducing core reprogramming and cell-cycle genes, leading to cell-cycle arrest and chromosomal abnormalities.