Can We Just Say : Transcription Second?

The striking correlation between genome topology and transcriptional activity has for decades made researchers revisit the question, "Does form follow function, or does function follow form?" In a new study, Hug et al. address this question by comparing the timing of zygotic genome activation to the emergence of genome structures during Drosophila embryogenesis

Regulation of disease-associated gene expression in the 3D genome

Genetic variation associated with disease often appears in non-coding parts of the genome. Understanding the mechanisms by which this phenomenon leads to disease is necessary to translate results from genetic association studies to the clinic. Assigning function to this type of variation is notoriously difficult because the human genome harbours a complex regulatory landscape with a dizzying array of transcriptional regulatory sequences, such as enhancers that have unpredictable, promiscuous and context-dependent behaviour. In this Review, we discuss how technological advances have provided increasingly detailed information on genome folding; for example, genome folding forms loops that bring enhancers and target genes into close proximity. We also now know that enhancers function within topologically associated domains, which are structural and functional units of chromosomes. Studying disease-associated mutations and chromosomal rearrangements in the context of the 3D genome will enable the identification of dysregulated target genes and aid the progression from descriptive genetic association results to discovering molecular mechanisms underlying disease

Can We Just Say : Transcription Second?

The striking correlation between genome topology and transcriptional activity has for decades made researchers revisit the question, "Does form follow function, or does function follow form?" In a new study, Hug et al. address this question by comparing the timing of zygotic genome activation to the emergence of genome structures during Drosophila embryogenesis

Cell-of-origin-specific 3D genome structure acquired during somatic cell reprogramming

Forced expression of reprogramming factors can convert somatic cells into induced pluripotent stem cells (iPSCs). Here we studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale topologically associated domain (TAD) repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic-cell-specific genome structures while establishing an embryonic stem-cell-like 3D genome. Yet, early passage iPSCs carry topological hallmarks that enable recognition of their cell of origin. These hallmarks are not remnants of somatic chromosome topologies. Instead, the distinguishing topological features are acquired during reprogramming, as we also find for cell-of-origin-dependent gene expression patterns.This work was supported by an NWO/CW TOP grant (714.012.002), an NWO VICI grant 724.012.003, a NanoNextNL grant, and a European Research Council Starting Grant (209700, ‘‘4C’’) to W.d.L.; a Ministerio de Educacion y Ciencia, SAF.2012-37167, Fundació La Marató TV3 120410, AGAUR SGR 1136, and European Research Council Synergy Grant (‘‘4D-Genome) to T.G.; and an ERC Stg (637587, ‘‘HAP-PHEN’’) to E.d.

Cell-of-origin-specific 3D genome structure acquired during somatic cell reprogramming

Forced expression of reprogramming factors can convert somatic cells into induced pluripotent stem cells (iPSCs). Here we studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale topologically associated domain (TAD) repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic-cell-specific genome structures while establishing an embryonic stem-cell-like 3D genome. Yet, early passage iPSCs carry topological hallmarks that enable recognition of their cell of origin. These hallmarks are not remnants of somatic chromosome topologies. Instead, the distinguishing topological features are acquired during reprogramming, as we also find for cell-of-origin-dependent gene expression patterns.This work was supported by an NWO/CW TOP grant (714.012.002), an NWO VICI grant 724.012.003, a NanoNextNL grant, and a European Research Council Starting Grant (209700, ‘‘4C’’) to W.d.L.; a Ministerio de Educacion y Ciencia, SAF.2012-37167, Fundació La Marató TV3 120410, AGAUR SGR 1136, and European Research Council Synergy Grant (‘‘4D-Genome) to T.G.; and an ERC Stg (637587, ‘‘HAP-PHEN’’) to E.d.

Regulation of disease-associated gene expression in the 3D genome

Genetic variation associated with disease often appears in non-coding parts of the genome. Understanding the mechanisms by which this phenomenon leads to disease is necessary to translate results from genetic association studies to the clinic. Assigning function to this type of variation is notoriously difficult because the human genome harbours a complex regulatory landscape with a dizzying array of transcriptional regulatory sequences, such as enhancers that have unpredictable, promiscuous and context-dependent behaviour. In this Review, we discuss how technological advances have provided increasingly detailed information on genome folding; for example, genome folding forms loops that bring enhancers and target genes into close proximity. We also now know that enhancers function within topologically associated domains, which are structural and functional units of chromosomes. Studying disease-associated mutations and chromosomal rearrangements in the context of the 3D genome will enable the identification of dysregulated target genes and aid the progression from descriptive genetic association results to discovering molecular mechanisms underlying disease