Biology subjects

Malecka, M.

Publications and source records attributed to Malecka, M..

3 recordsLinked to original sources

bioRxiv2026

Quantification of the effects of single nucleotide variants in NKX2.1 transcription factor binding sites

Transcription factors recognise and bind specific DNA sequence patterns in promoters and enhancers thereby regulating gene expression. Variations in the DNA sequence of transcription factor binding sites (TFBSs) can alter gene regulation and may disrupt development. The transcription factor NKX2.1 is a crucial regulator of thyroid, lung, and neural development. Mutations in its coding gene NKX2-1 may cause choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP, OMIM #610978). Most genetically solved patients carry mutations in the coding regions of NKX2-1 that affect DNA binding, while the majority of patients with CAHTP-like symptoms do not carry mutations in the NKX2-1 coding sequence. We hypothesise that variations in the DNA-sequence at promoter or enhancer sites to which the transcription factor NKX2.1 binds could cause disease as well. We employed EMSA-seq to quantify the effects of genetic variation on NKX2.1 binding strength and used this data to train neural network models to forecast the influence of DNA variation on NKX2.1 binding. We validated our models using microscale thermophoresis, X-ray crystallography, and publicly available ChIP-seq data sets. The neural networks were able to detect TFBSs in ChIP-seq data and can thus be used to evaluate whole genome sequencing data of CAHTP-patients in order to prioritise potential disease-causing variants in regulatory elements. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/708450v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@167cedeorg.highwire.dtl.DTLVardef@3e5291org.highwire.dtl.DTLVardef@19eb7f9org.highwire.dtl.DTLVardef@1404057_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism.

IP3 receptor (IP3R)-mediated Ca2+ transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca2+ uptake and oxidative metabolism and is linked to different pathologies, including Parkinsons disease (PD). The dependence of Ca2+ transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically-encoded Ca2+ indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of [~]20 nm is optimal for Ca2+ transfer and mitochondrial oxidative metabolism due to enrichment of IP3R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced which correlated with a reduction of mitochondrial Ca2+ uptake. Our work determines with precision the optimal distance for Ca2+ flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.

cell biology↗

bioRxiv2021

Potent but transient immunosuppression of T-cells is a general feature of erythroid progenitor cells

CD71+ erythroid cells (CECs) have been recently recognized in both neonates and cancer patients as potent immunoregulatory cells. Here, we show that in mice early-stage CECs expand in anemia, have high levels of arginase 2 (ARG2) and reactive oxygen species (ROS). In the spleens of anemic mice, CECs expansion-induced L-arginine depletion suppresses T-cell responses. In humans with anemia, CECs expand and express ARG1 and ARG2 that suppress T-cells IFN-{gamma} production. Moreover, bone marrow CECs from healthy human donors suppress T-cells proliferation. CECs differentiated from peripheral blood mononuclear cells potently suppress T-cell activation, proliferation, and IFN-{gamma} production in an ARG- and ROS-dependent manner. These effects are the most prominent for early-stage CECs (CD71highCD235adim cells). The suppressive properties disappear during erythroid differentiation as more differentiated CECs and mature erythrocytes lack significant immunoregulatory properties. Our studies provide a novel insight into the role of CECs in the immune response regulation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/427109v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@136fbd8org.highwire.dtl.DTLVardef@d05d00org.highwire.dtl.DTLVardef@189baceorg.highwire.dtl.DTLVardef@1472b2b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗