Combinatorial profiling of multiple histone modifications and transcriptome in single cells using scMTR-seq [bulk_DNA]

Profiling combinations of histone modifications identifies gene regulatory elements in different states and discovers features controlling transcriptional and epigenetic programmes. However, efforts to map chromatin states in defined cell types are hindered by the lack of methods that can profile multiple histone modifications together with transcriptome in individual cells. Here we describe single-cell Multi-Targets and mRNA sequencing (scMTR-seq), which enables simultaneous profiling of six histone modifications and transcriptome in single cells. As a proof of concept, we apply scMTR-seq to uncover the dynamics of chromatin state change during human endoderm differentiation. We also use scMTR-seq to produce lineage-resolved chromatin maps and gene regulatory networks in mouse blastocysts, revealing striking epigenetic asymmetries at gene regulatory regions between the three embryo lineages. We identify the transcription factor Trps1 as a potential repressor in epiblast cells of trophectoderm-associated enhancer networks and their target genes. Together, scMTR-seq enables investigation of combinatorial epigenetic modalities in low-cell number and heterogeneous samples. Overall design: We develop MTR-seq (multi-targets and mRNA sequencing), a multiomics sequencing technology that can simultaneously profile over six histone modifications and transcriptome in the same sample.