In addition to storage of genetic information, DNA can also catalyze various reactions. RNA-cleaving DNAzymes are the catalytic DNAs discovered the earliest, and they can cleave RNAs in a sequence-specific manner. Owing to their great potential in medical therapeutics, virus control, and gene silencing for disease treatments, RNA-cleaving DNAzymes have been extensively studied; however, the mechanistic understandings of their substrate recognition and catalysis remain elusive. Here, we report three catalytic form 8–17 DNAzyme crystal structures. 8–17 DNAzyme adopts a V-shape fold, and the Pb2+ cofactor is bound at the pre-organized pocket. The structures with Pb2+ and the modification at the cleavage site captured the pre-catalytic state of the RNA cleavage reaction, illustrating the unexpected Pb2+-accelerated catalysis, intrinsic tertiary interactions, and molecular kink at the active site. Our studies reveal that DNA is capable of forming a compacted structure and that the functionality-limited bio-polymer can have a novel solution for a functional need in catalysis.
The human genome is tightly packaged into chromatin whose functional output depends on both one-dimensional (1D) local chromatin states and three-dimensional (3D) genome organization. Currently, chromatin modifications and 3D genome organization are measured by distinct assays. An emerging question is whether it is possible to deduce 3D interactions by integrative analysis of 1D epigenomic data and associate 3D contacts to functionality of the interacting loci. Here we present EpiTensor, an algorithm to identify 3D spatial associations within topologically associating domains (TADs) from 1D maps of histone modifications, chromatin accessibility and RNA-seq. We demonstrate that active promoter–promoter, promoter–enhancer and enhancer–enhancer associations identified by EpiTensor are highly concordant with those detected by Hi-C, ChIA-PET and eQTL analyses at 200 bp resolution. Moreover, EpiTensor has identified a set of interaction hotspots, characterized by higher chromatin and transcriptional activity as well as enriched TF and ncRNA binding across diverse cell types, which may be critical for stabilizing the local 3D interactions.
Spinal cord injury (SCI) is one of serious traumatic diseases of the central nervous system and has no effective treatment because of its complicated pathophysiology. Tissue engineering strategy which contains scaffolds, cells, and growth factors can provide a promising treatment for SCI. Hydrogel that has 3D network structure and biomimetic microenvironment can support cellular growth and embed biological macromolecules for sustaining release. Dental pulp stem cells (DPSCs), derived from cranial neural crest, possess mesenchymal stem cell (MSC) characteristics and have an ability to provide neuroprotective and neurotrophic properties for SCI treatment. Basic fibroblast growth factor (bFGF) is able to promote cell survival and proliferation and also has beneficial effect on neural regeneration and functional recovery after SCI. Herein, a thermosensitive heparin-poloxamer (HP) hydrogel containing DPSCs and bFGF was prepared, and the effects of HP-bFGF-DPSCs on neuron restoration after SCI were evaluated by functional recovery tests, western blotting, magnetic resonance imaging (MRI), histology evaluation, and immunohistochemistry. The results suggested that transplanted HP hydrogel containing DPSCs and bFGF had a significant impact on spinal cord repair and regeneration and may provide a promising strategy for neuron repair, functional recovery, and tissue regeneration after SCI.
Supplementary data are available at Bioinformatics online.
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