Cell-type specialization is encoded by specific chromatin topologies.

The three-dimensional (3D) structure of chromatin is intrinsically associated with gene regulation and cell function. Methods based on chromatin conformation capture have mapped chromatin structures in neuronal systems such as in vitro differentiated neurons, neurons isolated through fluorescence-activated cell sorting from cortical tissues pooled from different animals and from dissociated whole hippocampi. However, changes in chromatin organization captured by imaging, such as the relocation of Bdnf away from the nuclear periphery after activation, are invisible with such approaches.

The dynamics of chromatin architecture in brain development and function.

The brain comprises many different cell types with specialized functions which respond and adapt to the continuously changing environment, through tight spatiotemporal regulation of gene expression. The three-dimentional (3D) organisation of the genome is increasingly recognized as a major feature of gene regulation in brain cells, for the activation, repression and poising of gene expression, and in coupling transcription with RNA processing and transport. Here, we discuss the importance of dynamic chromatin organisation in the developmental patterning of the brain, and its role in fine tuning brain activity and plasticity.

Evolving methodologies and concepts in 4D nucleome research.

The genome requires tight regulation in space and time to maintain viable cell functions. Advances in our understanding of the 3D genome show a complex hierarchical network of structures, involving compartments, membraneless bodies, topologically associating domains, lamina associated domains, protein- or RNA-mediated loops, enhancer-promoter contacts, and accessible chromatin regions, with chromatin state regulation through epigenetic and transcriptional mechanisms. Further technology developments are poised to increase genomic resolution, dissect single-cell behaviors, including in vivo dynamics of genome folding, and provide mechanistic perspectives that identify further 3D genome players by integrating multiomics information.

Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis.

The regulatory specificity of enhancers and their interaction with gene promoters is thought to be controlled by their sequence and the binding of transcription factors. By studying Pitx1, a regulator of hindlimb development, we show that dynamic changes in chromatin conformation can restrict the activity of enhancers. Inconsistent with its hindlimb-restricted expression, Pitx1 is controlled by an enhancer (Pen) that shows activity in forelimbs and hindlimbs.

Mutations in cause a recessive form of central hypoventilation with autonomic dysfunction.

Background: Congenital central hypoventilation syndrome (CCHS) is a rare life-threatening disorder of respiratory and autonomic regulation. It is classically caused by dominant mutations in the transcription factor . The objective of the present study was to identify the molecular cause of a recessive form of central hypoventilation with autonomic dysfunction.

Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.

The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK. ZAK is a member of the MAPKKK family with no known role in limb development.

Deletions, Inversions, Duplications: Engineering of Structural Variants using CRISPR/Cas in Mice.

Structural variations (SVs) contribute to the variability of our genome and are often associated with disease. Their study in model systems was hampered until now by labor-intensive genetic targeting procedures and multiple mouse crossing steps. Here we present the use of CRISPR/Cas for the fast (10 weeks) and efficient generation of SVs in mice.

Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome.

Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.