ENAapplication/xmlftp.sra.ebi.ac.uk/vol1/fastq/SRR156/007/SRR1561747/SRR1561747.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR156/006/SRR1561746/SRR1561746.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR156/008/SRR1561748/SRR1561748.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR156/005/SRR1561745/SRR1561745.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR156/009/SRR1561749/SRR1561749.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR156/000/SRR1561750/SRR1561750.fastq.gzprimaryOK2000000GenomicsMultiomicsBioinformatics, The Babraham Institutehttps://www.ebi.ac.uk/ena/browser/view/PRJNA259876Homo sapiensCurrent human pluripotent stem cells lack the transcription factor circuitry that governs the ground state of mouse embryonic stem cells (ESC). Here we report that short-term expression of two components, NANOG and KLF2, is sufficient to ignite other elements of the network and reset the human pluripotent state. Inhibition of ERK and protein kinase C signalling sustains a transgene-independent rewired state. Reset cells self-renew continuously without ERK signalling, are phenotypically stable and karyotypically intact. They differentiate in vitro and form teratomas in vivo. Metabolism is reprogrammed in reset cells with activation of mitochondrial respiration as in ESC. DNA methylation is dramatically reduced and transcriptome state is globally realigned across multiple cell lines. Depletion of ground state transcription factors, TFCP2L1 or KLF4 has marginal impact on conventional human pluripotent stem cells, but collapses the reset state. These findings demonstrate feasibility of installing and propagating functional control circuitry for ground state pluripotency in human cells. Overall design: DNA methylation analysis in Conventional and Reset human embryonic stem cells by whole genome bisulfite sequencing, in triplicate, using the Illumina platformENAF14P3.4, transcription factor, RNA polymerase II core promoter proximal region sequence-specific binding, T-cell leukemia, Controlling, human being, reference sample, AGL4, F14P3_4, F10N7_150, zinc ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, homeobox 1, SEPALLATA 2, sequence-specific DNA binding RNA polymerase II transcription factor activity, metal ion regulated core promoter proximal region sequence-specific binding, metal ion regulated sequence-specific DNA binding RNA polymerase II transcription factor activity, copper ion regulated core promoter proximal region sequence-specific binding, RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity, man, Transcription factor, F10N7.150, transcription factor activity, zinc ion regulated core promoter proximal region sequence-specific DNA binding, RNA polymerase II proximal promoter sequence-specific DNA binding, copper ion regulated proximal promoter sequence-specific DNA binding, RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity, AGAMOUS-like 4, copper ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, RNA polymerase II transcription factor activity, zinc ion regulated proximal promoter sequence-specific DNA binding, sequence-specific transcription regulatory region DNA binding RNA polymerase II transcription factor recruiting transcription factor activity, sequence-specific DNA binding, sequence-specific distal enhancer binding RNA polymerase II transcription factor activity, metal ion regulated sequence-specific DNA binding, metal ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, human., KNOTTED1-like homeobox gene 5, metal ion regulated proximal promoter sequence-specific DNA binding, TRANSCRIPTION FACTOR, Controlled, sequence-specific transcription regulatory region DNA binding, RNA polymerase II distal enhancer sequence-specific bindinghuman being, human., man0.00.00.00.00.00falseHomo sapiensResetting Transcription Factor Control Circuitry Towards Ground State Pluripotency In Human2022-07-172014-09-10PRJNA259876GSE60945252154869606