Biology subjects

Mall, M.

Publications and source records attributed to Mall, M..

4 recordsLinked to original sources

bioRxiv2021

Post-entry, spike-dependent replication advantage of B.1.1.7 and B.1.617.2 over B.1 SARS-CoV-2 in an ACE2-deficient human lung cell line

Epidemiological data demonstrate that SARS-CoV-2 variants of concern (VOC) B.1.1.7 and B.1.617.2 are more transmissible and infections are associated with a higher mortality than non-VOC virus infections. Phenotypic properties underlying their enhanced spread in the human population remain unknown. B.1.1.7 virus isolates displayed inferior or equivalent spread in most cell lines and primary cells compared to an ancestral B.1 SARS-CoV-2, and were outcompeted by the latter. Lower infectivity and delayed entry kinetics of B.1.1.7 viruses were accompanied by inefficient proteolytic processing of spike. B.1.1.7 viruses failed to escape from neutralizing antibodies, but slightly dampened induction of innate immunity. The bronchial cell line NCI-H1299 supported 24- and 595-fold increased growth of B.1.1.7 and B.1.617.2 viruses, respectively, in the absence of detectable ACE2 expression and in a spike-determined fashion. Superior spread in NCI-H1299 cells suggests that VOCs employ a distinct set of cellular cofactors that may be unavailable in standard cell lines.

microbiology↗

bioRxiv2021

MEOX2 homeobox gene promotes growth of malignant gliomas

Glioblastoma (GBM) is an aggressive tumor that frequently exhibits gain of chromosome 7, loss of chromosome 10 and aberrantly activated receptor tyrosine kinase signaling pathways. Here, we identify mesenchyme homeobox 2 (MEOX2) on chromosome 7 with increased expression in GBM as a salient oncogenic transcription factor. Specifically, we show that MEOX2 overexpression leads to increased ERK phosphorylation, and we identify a phosphorylation site on MEOX2 that regulates its transcriptional activity by altering its subnuclear localization. We show that MEOX2 overexpression can lead to increased growth in GBM implantation models and cooperates with loss of p53 and PTEN in cerebral organoid models of human malignant gliomas to induce cell proliferation. Furthermore, using high-throughput genomics, we identify transcriptional target genes of MEOX2 in patient-derived GBM tumorsphere models and a fresh frozen GBM tumor. These analyses show that MEOX2 activates several oncogenic pathways involved in MAPK signaling and extracellular matrix organization. Furthermore, MEOX2 binds to oncogenic ETS factors and known glioma oncogenes such as FABP7. In total, we reveal a novel role for MEOX2 in GBM initiation and progression and demonstrate that MEOX2 can enhance ERK signaling through a feed-forward mechanism. Significance StatementGlioblastoma (GBM) harbors gain of chromosome 7 as an early driver event. In this study, we show that mesenchyme homeobox 2 (MEOX2), an aberrantly upregulated transcription factor on chromosome 7, is an oncogene in human glioblastoma. In contrast to GBM, MEOX2 expression is very low in normal brain. We show that MEOX2 cooperates with p53 and PTEN loss to promote tumor initiation in cerebral organoid models. In addition, we identify direct and indirect molecular targets of MEOX2 and demonstrate its role in activating the ERK signaling cascade. These findings identify a novel oncogene in GBM and highlight the transcriptional networks hijacked by these tumors to activate signaling pathways central to GBM biology.

cancer biology↗

bioRxiv2020

THE DYNAMIC INTERPLAY BETWEEN HOMEODOMAIN TRANSCRIPTION FACTORS AND CHROMATIN ENVIRONMENT REGULATES PRONEURAL FACTOR OUTCOMES

Generation of neurons of vast diversity involves early spatial and temporal patterning of the neuronal precursors by morphogenic gradients and combinatorial expression of transcription factors. While the proneuronal function of the basic-helix-loop-helix (bHLH) transcription factor Ngn2 is well established, its role in neuronal subtype specification remains unclear. Here, we found that coexpressing NGN2 with the forebrain homeobox factor EMX1 converts human pluripotent stem cells into a highly homogeneous glutamatergic forebrain neurons without partial cholinergic and monoaminergic gene programs observed in cells infected with NGN2 only. Our molecular characterization revealed that transcriptional output and genomic targeting of Ngn2 is altered by co-factors such as EMX1 explaining the more focused subtype specification. Ngn2 function is less modified by the chromatin environment and does not affect regionalization of pre-patterned neural progenitors. These results enable improved strategies for generating a plethora of defined neuronal subpopulations from pluripotent stem cells for therapeutic or disease-modeling purposes. HighlightsO_LINGN2 converts human ES cells into glutamatergic neurons some of which co-express a partial cholinergic program C_LIO_LINGN2 directly binds to and activates ISL1 in ES cells which together with PHOX2A/B induce cholinergic genes C_LIO_LIAnterior-posterior regionalization affects NGN2 binding and transcriptional output but does not focus subtype specification C_LIO_LIForebrain homeobox factors including EMX1 and FOXG1 redirect NGN2 chromatin binding and repress posterior and cholinergic genes, resulting in homogeneous forebrain excitatory neurons C_LI

genomics↗

bioRxiv2019

Nuclear lamin B is crucial to the nuclear envelope integrity and extracellular trap release in neutrophils

Its not clear how nuclear envelope (NE) is ruptured for chromatin externalization during NETosis. The membrane rupture during neutrophil NET release was described as a membrane lysis process, this notion, however, has been questioned. Here, we found that lamin B, the structural NE component, was involved in NETosis. Unexpectedly, lamin B was not fragmented by destructive proteolysis, but rather disassembled into its intact full-length molecule, in NETotic cells with ruptured NE. In the mechanistic study, our experiments demonstrated that cytosolic PKC translocated to the nucleus, where it serves as a NETotic lamin kinase to induce lamin B phosphorylation, following by lamina disassembly and NE rupture. To determine causality, we found that decreasing lamin B phosphorylation, by PKC inhibition or genetic deletion, or mutation at the PKC consensus phosphorylation sites of lamin B, attenuated extracellular trap formation. Importantly, strengthening NE by lamin B overexpression attenuated neutrophil NETosis in vivo and alleviated exhibition of NET-associated inflammatory cytokines in UVB irradiated skin of lamin B transgenic mice. These findings advance our understanding of NETosis process and elucidate a cellular mechanism that PKC-mediated lamin B phosphorylation drives nuclear envelope rupture for NET release in neutrophils.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC=\"FIGDIR/small/647529v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (49K):\norg.highwire.dtl.DTLVardef@7bd231org.highwire.dtl.DTLVardef@124bf6dorg.highwire.dtl.DTLVardef@19396ecorg.highwire.dtl.DTLVardef@9989cb_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗