Nuclear morphology is shaped by loop-extrusion programs.

It is well established that neutrophils adopt malleable polymorphonuclear shapes to migrate through narrow interstitial tissue spaces1-3. However, how polymorphonuclear structures are assembled remains unknown4. Here we show that in neutrophil progenitors, halting loop extrusion-a motor-powered process that generates DNA loops by pulling in chromatin5-leads to the assembly of polymorphonuclear genomes. Specifically, we found that in mononuclear neutrophil progenitors, acute depletion of the loop-extrusion loading factor nipped-B-like protein (NIPBL) induced the assembly of horseshoe, banded, ringed and hypersegmented nuclear structures and led to a reduction in nuclear volume, mirroring what is observed during the differentiation of neutrophils. Depletion of NIPBL also induced cell-cycle arrest, activated a neutrophil-specific gene program and conditioned a loss of interactions across topologically associating domains to generate a chromatin architecture that resembled that of differentiated neutrophils. Removing NIPBL resulted in enrichment for mega-loops and interchromosomal hubs that contain genes associated with neutrophil-specific enhancer repertoires and an inflammatory gene program. On the basis of these observations, we propose that in neutrophil progenitors, loop-extrusion programs produce lineage-specific chromatin architectures that permit the packing of chromosomes into geometrically confined lobular structures. Our data also provide a blueprint for the assembly of polymorphonuclear structures, and point to the possibility of engineering de novo nuclear shapes to facilitate the migration of effector cells in densely populated tumorigenic environments.

A regulatory network of microRNAs confers lineage commitment during early developmental trajectories of B and T lymphocytes.

The commitment of hematopoietic multipotent progenitors (MPPs) toward a particular lineage involves activation of cell type-specific genes and silencing of genes that promote alternate cell fates. Although the gene expression programs of early-B and early-T lymphocyte development are mutually exclusive, we show that these cell types exhibit significantly correlated microRNA (miRNA) profiles. However, their corresponding miRNA targetomes are distinct and predominated by transcripts associated with natural killer, dendritic cell, and myeloid lineages, suggesting that miRNAs function in a cell-autonomous manner. The combinatorial expression of miRNAs miR-186-5p, miR-128-3p, and miR-330-5p in MPPs significantly attenuates their myeloid differentiation potential due to repression of myeloid-associated transcripts. Depletion of these miRNAs caused a pronounced de-repression of myeloid lineage targets in differentiating early-B and early-T cells, resulting in a mixed-lineage gene expression pattern. De novo motif analysis combined with an assay of promoter activities indicates that B as well as T lineage determinants drive the expression of these miRNAs in lymphoid lineages. Collectively, we present a paradigm that miRNAs are conserved between developing B and T lymphocytes, yet they target distinct sets of promiscuously expressed lineage-inappropriate genes to suppress the alternate cell-fate options. Thus, our studies provide a comprehensive compendium of miRNAs with functional implications for B and T lymphocyte development.

Effect of Xylocarpus granatum Bark Extract on Amelioration of Hyperglycaemia and Oxidative Stress Associated Complications in STZ-Induced Diabetic Mice.

Xylocarpus granatum is a medicinal mangrove plant, traditionally used for the treatment of diarrhoea, cholera, fever, dyslipidaemia, inflammation, etc. The present study was aimed to evaluate the in vitro antidiabetic (α-glucosidase inhibition assay) and antioxidant (ABTS scavenging and metal chelating assay) activities of ethanol, methanol, and aqueous extracts of leaves and barks of X. granatum followed by in vivo antidiabetic and antioxidant evaluation of ethanol bark extracts in streptozotocin- (STZ-) induced diabetic mice. The in vitro evaluation revealed higher α-amylase inhibition and ABTS scavenging activities in ethanol bark extracts of X. granatum (XGEB). Administration of XGEB at 100 and 200 mg/kg BW doses to STZ-induced diabetic mice resulted in significant decrease (P < 0.05) in blood glucose, triglyceride (TG), total cholesterol (TC), serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transminase (SGPT), and urea levels in the serum of the extract administered groups as compared to diabetic control group. The levels of SOD, CAT, GPx, GR, and GST in liver along with LPx, SOD, GST, and GR activities in brain tissues were found to be ameliorated in XGEB treated diabetic mice. Histopathological alternations of liver tissues were also found to be restored in XGEB treated diabetic groups. The HPLC fingerprint analysis of XGEB revealed the presence of simple polyphenols, isoflavone, and flavonol-like compounds. The DSC and UV-VIS analysis also confirmed the presence of phenolic compounds in XGEB. The GC-MS analysis of XGEB showed the presence of a number of bioactive compounds. These results demonstrated the beneficial effect of XGEB in controlling hyperglycaemia and ameliorating oxidative stress associated complications associated with diabetes.