Biology subjects

Heino, J.

Publications and source records attributed to Heino, J..

9 recordsLinked to original sources

bioRxiv2025

P4HA3 is abundantly expressed during early embryonic development, but does not catalyze the formation of 4-hydroxyproline in type I collagen

4-Hydroxyproline (4Hyp) is crucially important for the collagen triple helix formation and its thermal stability. It is catalyzed by collagen prolyl 4-hydroxylases (C-P4Hs) that are 2{beta}2 tetramers consisting of two identical catalytic -subunits (encoded by P4HA1, P4HA2 and P4HA3) and two {beta}-subunits that are protein disulfide isomerases (PDI). The functions of isoenzymes I and II (P4HA1 and P4HA2) are widely studied but very little is currently known about the role of P4HA3. Here we show that P4ha1 is generally the most abundant isoform in mouse, whereas P4ha3 expression is tissue and developmental stage specific. P4ha3 expression is highest in the developing skeletal system and peaks at E12.5 together with the other isoforms. Postnatal P4ha3 expression is low and mainly present in calvaria, lung, heart and muscle. The P4ha3 expression virtually disappears at or after 1 week of age in all tissues studied. To evaluate the P4HA3 function in collagen synthesis, we produced cells that lack P4HA3 (P4ha3-/-) and cells that have P4HA3 as the only isoform (P4ha1-/-;P4ha2-/-) by CRISPR/Cas9. C-P4H activity assays indicated no 4Hyp formation in type I collagen by the P4ha1-/-;P4ha2-/- cells, suggesting that the remaining isoform P4HA3 does not participate in type I collagen synthesis. The P4ha3-/- cells secreted intact pepsin-resistant collagen that had a similar 4Hyp content and melting temperature as in WT cells, and the secreted collagen assembled correctly into supramolecular collagen fibrils. In conclusion, our results provide new insights into collagen biosynthesis and suggest that prolyl 4-hydroxylation of type I collagen is mediated by P4HA1 and P4HA2 but not by P4HA3.

biochemistry↗

bioRxiv2025

Jagged1 regulates extracellular matrix deposition and remodeling in triple-negative breast cancer

The extracellular matrix (ECM) in the tumor microenvironment plays an essential role in cancer progression. High expression of Jagged1 correlates with poor patient survival and promotes in vivo tumor growth and invasion in triple-negative breast cancer (TNBC). Using transcriptomics, proteomics, and imaging of cancer cell/fibroblast co-cultures, both in vitro and in vivo, we demonstrate that Jagged1-mediated crosstalk between TNBC cells and fibroblasts enhances myofibroblast activation, collagen deposition, and alignment of ECM fibers. Jagged1 increases transforming growth factor beta (TGF{beta}) activity in fibroblast co-cultures and the Jagged1-induced ECM alignment can be prevented by a TGF{beta} inhibitor. Thus, Jagged1 regulates ECM remodeling upstream of TGF{beta}. Furthermore, higher substrate stiffness increases Jagged1 expression, pointing towards a feed-forward loop between Jagged1, ECM stiffness, and TGF{beta}. With the emergence of safe therapeutics targeting specific Notch ligands and receptors, Jagged1 modulation may offer a path to therapeutically target invasive breast cancer.

cancer biology↗

bioRxiv2023

Collagen prolyl 4-hydroxylases have sequence specificity towards different X-Pro-Gly triplets

Formation of 4-hydroxyproline (4Hyp) in -X-Pro-Gly- collagen sequences is essential for the thermal stability of collagen molecules. 4Hyp formation is catalyzed by collagen prolyl 4-hydroxylases (C- P4H). Here we identify specific roles for the two main C-P4H isoenzymes by 4Hyp analysis of type I and IV collagens. Loss of C-P4H-I mainly affected prolines preceded by an X-position amino acid with a positively charged or a polar uncharged side chain. In contrast, loss of C-P4H-II affected triplets with a negatively charged glutamate or aspartate in the X-position, and their hydroxylation was found to be important as loss of C-P4H-II alone resulted in reduced collagen melting temperature and altered assembly of collagen fibrils and basement membrane. The C-P4H isoenzyme differences in substrate specificity were explained by selective substrate binding to the active site resulting in differences in Km and Vmax values. In conclusion, this study provides a molecular level explanation for the need of multiple C-P4H isoenzymes to generate collagen molecules capable to assemble into intact extracellular matrix structures.

molecular biology↗

bioRxiv2022

Temporal variation of patch connectivity determines biodiversity recovery from recurrent disturbances

Understanding the capacity of ecological systems to withstand and recover from disturbances is a major challenge for ecological research in the context of environmental change. Disturbances have multi-scale effects: they can cause species extinctions locally and alter connectivity between habitat patches at the metacommunity level. Yet, our understanding of how disturbances influence landscape connectivity remains limited. To fill this gap, we develop a novel connectivity index that integrates the temporal variation of patch connectivity induced by disturbances, which can be applied to any spatially-structured habitat. We then combine this index with a metacommunity model to specifically investigate biodiversity recovery from drying events in river network metacommunities. We demonstrate that patch connectivity explains variations of species richness between groups of organisms with contrasting dispersal modes and captures the effect of drying intensity (i.e., fraction of patches that dry-up) and drying location on community recovery. As a general rule, loss of patch connectivity decreases community recovery, regardless of patch location in the river network, dispersal mode, or drying intensity. Local communities of flying organisms maintained higher patch connectivity in drying river networks compared to organisms with strictly aquatic dispersal, which explained the higher recovery capacity of this group from drying events. The general relationship between patch connectivity and community recovery we found can be applied to any spatial network subject to temporal variation of connectivity, thus providing a powerful tool for biodiversity management in dynamic landscapes.

ecology↗

bioRxiv2021

Embigin deficiency leads to delayed embryonic lung development and high neonatal mortality

Embigin (gp70), a transmembrane glycoprotein, has been shown to regulate hematopoietic stem cell and progenitor cell niche. Still, little is known about its expression and function in other organ systems during development or adulthood. By combining immunofluorescence, RNA sequencing, and in vivo mouse models, we show that embigin is highly expressed during development and in adult lung, kidney, epididymis, skin, and testis. Adult Emb-/- mice have a normal lifespan and fertility without apparent pathologies. In contrast, the Emb-/- embryos are significantly smaller than their WT littermates. Markedly increased mortality of the Emb-/- embryos is seen especially during the neonatal period. Embigin is present in the placenta, but placental morphology and gene expression patterns stay unaltered. At E17.5, Emb-/- mice show defective morphogenesis of the lung, low alkaline phosphatase activity in amniotic fluid, and remarkable activation of genes involved in cell proliferation in the lungs. Thus, lung underdevelopment explains the high neonatal mortality. Our work demonstrates the crucial role of embigin during development, and it paves the way to further characterization of embigin in specific organ systems in development and homeostasis. Summary statementEmbigin is a basigin-group transmembrane glycoprotein. In vivo mouse model shows that embigin is crucial for embryonic lung development and neonatal survival.

developmental biology↗

bioRxiv2021

Distance decay 2.0 - a global synthesis of taxonomic and functional turnover in ecological communities.

Understanding the variation in community composition and species abundances, i.e., {beta}-diversity, is at the heart of community ecology. A common approach to examine {beta}-diversity is to evaluate directional turnover in community composition by measuring the decay in the similarity among pairs of communities along spatial or environmental distances. We provide the first global synthesis of taxonomic and functional distance decay along spatial and environmental distance by analysing 149 datasets comprising different types of organisms and environments. We modelled an exponential distance decay for each dataset using generalized linear models and extracted r2 and slope to analyse the strength and the rate of the decay. We studied whether taxonomic or functional similarity has stronger decay across the spatial and environmental distances. We also unveiled the factors driving the rate of decay across the datasets, including latitude, spatial extent, realm, and organismal features. Taxonomic distance decay was stronger along spatial and environmental distances compared with functional distance decay. The rate of taxonomic spatial distance decay was the fastest in the datasets from mid-latitudes while the rate of functional decay increased with latitude. Overall, datasets covering larger spatial extents showed a lower rate of decay along spatial distances but a higher rate of decay along environmental distances. Marine ecosystems had the slowest rate of decay. This synthesis is an important step towards a more holistic understanding of patterns and drivers of taxonomic and functional {beta}-diversity.

ecology↗

bioRxiv2020

DISPERSE: A trait database to assess the dispersal potential of aquatic macroinvertebrates

Dispersal is an essential process in population and community dynamics, but is difficult to measure in the field. In freshwater ecosystems, information on biological traits related to organisms morphology, life history and behaviour provides useful dispersal proxies, but information remains scattered or unpublished for many taxa. We compiled information on multiple dispersal-related biological traits of European aquatic macroinvertebrates in a unique resource, the DISPERSE database. DISPERSE includes 39 trait categories grouped into nine dispersal-related traits for 480 taxa, including Annelida, Mollusca, Platyhelminthes, and Arthropoda such as Crustacea and Insecta, generally at the genus level. Information within DISPERSE can be used to address fundamental questions in metapopulation ecology, metacommunity ecology, macroecology and evolutionary ecology research. Information on dispersal proxies can be applied to improve predictions of ecological responses to global change, and to inform improvements to biomonitoring and conservation management strategies. The diverse sources used in DISPERSE complement existing trait databases by providing new information on dispersal traits, most of which would not otherwise be accessible to the scientific community.

ecology↗

bioRxiv2019

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

Gene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-{beta}-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encoding KRAS, MYC and FAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosis in vitro and in vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/{beta}-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.\n\nGraphical Summary\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC=\"FIGDIR/small/594184_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (52K):\norg.highwire.dtl.DTLVardef@20c737org.highwire.dtl.DTLVardef@1f714faorg.highwire.dtl.DTLVardef@823560org.highwire.dtl.DTLVardef@7e6219_HPS_FORMAT_FIGEXP M_FIG C_FIG Key PointsO_LIHigh grade serous ovarian carcinoma tumors contain PTK2 (FAK) 8q24.3 gains associated with prognostic differences.\nC_LIO_LIKMF, a new murine ovarian cancer model with K-Ras, Myc, and FAK gene gains and intrinsic platinum resistance.\nC_LIO_LIFAK activation in tumors surviving platinum chemotherapy promotes cancer stem cell survival.\nC_LIO_LIFAK facilitates a {beta}-catenin-Myc signaling axis controlling gene expression supporting platinum resistance.\nC_LIO_LIFAK activity is essential for KMF tumor growth and is a targetable cellular adaptation of platinum resistance.\nC_LI

cancer biology↗

bioRxiv2019

Community size affects the signals of selection and ecological drift on biodiversity

Ecological drift can override the effects of deterministic niche selection on small populations and drive the assembly of small communities. We tested the hypothesis that smaller local communities are more dissimilar among each other because of ecological drift than larger communities, which are mainly structured by niche selection. We used a unique, comprehensive dataset on insect communities sampled identically in a total of 200 streams in climatically different regions (Brazil and Finland) that differ in community size by fivefold. Null models allowed us to estimate the magnitude to which beta diversity deviates from the expectation under a random assembly process while taking differences in species richness and relative abundance into account, i.e., beta deviation. Beta diversity of small tropical communities was consistently higher but closer to null expectations than {beta}-diversity of large communities. However, although {beta}-deviation and community size were strongly related in both regions, the direction of the relationship varied according to dissimilarity metrics. While incidence-based {beta}-diversity was lower than expected (communities were less dissimilar than null expectations) and negatively related to community size in Brazil, abundance-based {beta}-diversity was higher than expected (communities were more dissimilar than null expectations) and positively related to community size in both regions. We suggest that ecological drift drives variation in small communities by increasing the chances of species with low abundance and narrow distribution to occur within the metacommunity. Also, while weak niche selection and high dispersal rates likely reduced variation in community structure among large tropical streams, niche selection was likely sufficient to cause non-random variations in the relative abundances of genera among large communities in both regions. Habitat destruction, overexploitation, pollution, and reductions in connectivity have been reducing the size of biological communities. These environmental pressures will make smaller communities more vulnerable to novel conditions and render community dynamics more unpredictable, as random demographic processes should prevail under these conditions. Incorporation of community size into ecological models should provide conceptual, empirical and applied insights into a better understanding of the processes driving changes in biodiversity.

ecology↗