Transcription factor-induced reprogramming of specialized cells into other cell types and to pluripotency has revolutionized our thinking about cell plasticity, differentiation, and stem cells. The ...recent advances in this area were enabled by the confluence of a number of experimental breakthroughs that took place over the past 60 years. In this article, I give a historical and personal perspective of the events that set the stage for our current understanding of cellular reprogramming.
How cells adopt different identities has long fascinated biologists. Signal transduction in response to environmental cues results in the activation of transcription factors that determine the ...gene-expression program characteristic of each cell type. Technological advances in the study of 3D chromatin folding are bringing the role of genome conformation in transcriptional regulation to the fore. Characterizing this role of genome architecture has profound implications, not only for differentiation and development but also for diseases including developmental malformations and cancer. Here we review recent studies indicating that the interplay between transcription and genome conformation is a driving force for cell-fate decisions.
Laser materials processing with ultra-short pulses allows very precise and high quality results with a minimum extent of the thermally affected zone. However, with increasing average laser power and ...repetition rates the so-called heat accumulation effect becomes a considerable issue. The following discussion presents a comprehensive analytical treatment of multi-pulse processing and reveals the basic mechanisms of heat accumulation and its consequence for the resulting processing quality. The theoretical findings can explain the experimental results achieved when drilling microholes in CrNi-steel and for cutting of CFRP. As a consequence of the presented considerations, an estimate for the maximum applicable average power for ultra-shorts pulsed laser materials processing for a given pulse repetition rate is derived.
Chromosomal architecture is known to influence gene expression, yet its role in controlling cell fate remains poorly understood. Reprogramming of somatic cells into pluripotent stem cells (PSCs) by ...the transcription factors (TFs) OCT4, SOX2, KLF4 and MYC offers an opportunity to address this question but is severely limited by the low proportion of responding cells. We have recently developed a highly efficient reprogramming protocol that synchronously converts somatic into pluripotent stem cells. Here, we used this system to integrate time-resolved changes in genome topology with gene expression, TF binding and chromatin-state dynamics. The results showed that TFs drive topological genome reorganization at multiple architectural levels, often before changes in gene expression. Removal of locus-specific topological barriers can explain why pluripotency genes are activated sequentially, instead of simultaneously, during reprogramming. Together, our results implicate genome topology as an instructive force for implementing transcriptional programs and cell fate in mammals.
Aluminum (AA6016) sheets were welded in overlap configuration to investigate the influence of different beam oscillation patterns on the resulting temperature gradient, the local solidification rate ...and the resulting grain structure and to compare the results with those obtained with the conventional rectilinear welding. Two pyrometers were used to experimentally determine the temperature gradient. The weld pool boundaries on the surface plane of the work piece were determined by image processing of high speed videos, in order to evaluate the local solidification rates. Metallographic analysis of the weld seams proved that laser beam oscillation during welding can be used to reliably form an equiaxed dendritic grain structure, which reduces the susceptibility to the formation of hot cracks.
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•Experimental determination of local solidification rates during welding•Image processing to determine changes of weld pool geometry•Identification of local extrema of the solidification rate•Measurement of the temperature gradient in the solidification zone•Connection between the local solidification conditions and the grain structure
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.
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•The 3D genome topology of four somatic cell types varies greatly and differs from ESCs•The 3D genomes of iPSCs from different founders and of ESCs are overall highly similar•Early-passage iPSCs show subtle but reproducible founder-dependent 3D differences•The distinctive topology features of iPSCs are acquired during reprogramming
Krijger et al. report that the reprogramming of four somatic cell types with highly distinct 3D genomes results in pluripotent cells with largely identical, ESC-like, genome conformations carrying founder-dependent topological hallmarks. The latter are not remnants of somatic chromosome topologies but are acquired during reprogramming in a cell-of-origin-dependent manner.
The meeting covered a plethora of rapidly evolving approaches and areas, such as organoid cultures modeling tissues and organs; stem cell-specific metabolites revealing new signaling pathways; ...single-cell technologies discovering new cell types and exploring stem cell niche interactions; novel methods studying stem cells in aging and cancer; lineage-tracing experiments exploring cell plasticity of tissues before and after injury; epigenetic studies illuminating cell reprogramming; new protocols improving cells for regenerative purposes; and several other timely and exciting topics.
The meeting covered a plethora of rapidly evolving approaches and areas, such as organoid cultures modeling tissues and organs; stem cell-specific metabolites revealing new signaling pathways; single-cell technologies discovering new cell types and exploring stem cell niche interactions; novel methods studying stem cells in aging and cancer; lineage-tracing experiments exploring cell plasticity of tissues before and after injury; epigenetic studies illuminating cell reprogramming; new protocols improving cells for regenerative purposes; and several other timely and exciting topics.
Histone methylation is required for the establishment and maintenance of gene expression patterns that determine cellular identity, and its perturbation often leads to aberrant development and ...disease. Recruitment of histone methyltransferases (HMTs) to gene regulatory elements (GREs) of developmental genes is important for the correct activation and silencing of these genes, but the drivers of this recruitment are largely unknown. Here we propose that lineage-instructive transcription factors (Lin-TFs) act as general recruiters of HMT complexes to cell type-specific GREs through protein–protein interactions. We also postulate that the specificity of these interactions is dictated by Lin-TF post-translational modifications (PTMs), which act as a ‘transcription factor code’ that can determine the directionality of cell fate decisions during differentiation and development.
Lineage-instructive transcription factors (Lin-TFs) are able to drive cell fate changes by binding to sequence-specific motifs in gene regulatory elements (GREs).Histone methyltransferases (HMTs) decorate histones at different GREs in different cell types throughout development, regulating lineage-restricted gene activation and silencing.Several mechanisms for HMT recruitment to lineage-specific GREs have been described, but there is no clear consensus in the field.Time-resolved analysis shows that transcription factor binding often precedes histone modification changes in the neighboring nucleosomes.Lin-TFs can interact with HMT complexes.Lin-TFs are targets of a large number of modifying enzymes. Some of the resulting PTMs have been reported to modulate interactions of Lin-TFs with other proteins.
One of the major goals of linguistics is to delineate the possible range of variation across languages. Recent work has identified a surprising number of typological gaps in a variety domains. In ...morphology, this includes stem suppletion, person pronoun syncretism, case syncretism, and noun stem allomorphy. In morphosyntax, only a small number of all conceivable Person Case Constraints and Gender Case Constraints are found. While various proposals have been put forward for each individual domain, few attempts have been made to give a unified explanation of the limited typology across all domains. This paper presents a novel account that deliberately abstracts away from the usual details of grammatical description in order to provide a domain-agnostic explanation of the limits of typological variation. This is achieved by combining prominence hierarchies, e.g. for person and case, with mappings from those hierarchies to the relevant output forms. As the mappings are required to be monotonic, only a fraction of all conceivable patterns can be instantiated.
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