Biology subjects

Lorzadeh, A.

Publications and source records attributed to Lorzadeh, A..

4 recordsLinked to original sources

bioRxiv2026

CDX2 Drives Divergent Regional Programs During Intestinal Development and Redeploys Them During Regeneration

Region-specific transcription factors (TFs) establish small intestinal and colonic identity, yet what activates their region-specific expression during development is unresolved. Moreover, discrete fetal gene sets reactivate during post-injury regeneration, but their full scope, and what reactivates the programs required to restore regional identity and tissue structure, remain unclear. By determining CDX2 and partner TF binding, enhancer activity, and gene expression dynamics across intestinal regions, in stem and differentiating cells, and through development and adult regeneration, here we show that CDX2, despite uniform expression across the fetal and adult intestinal epithelium, organizes a hierarchical enhancer network. This network cooperates with partner factors such as CTCF to establish a shared, plastic fetal enhancer landscape, which resolves into region-specific programs upstream of regional TFs. During regeneration, rather than reactivating a general fetal state, CDX2 selectively rebinds many region-specific and common enhancers for genes associated with fetal cell-motility and tissue-morphogenesis signatures along with a more recently active adult stem-cell program, each deployed across distinct crypt tiers. CDX2 thus functions as a central, context-responsive regulator, deploying fetal, adult stem-cell differentiation, and regenerative programs as tissue context requires.

developmental biology↗

bioRxiv2026

Epigenetic Gatekeeping of Intestinal Stem Cell Transformation

Widespread cell plasticity recognized in fetal intestinal epithelium is preserved in limited fashion in Wnt-responsive adult stem cells and contributes to tumour initiation, progression, and relapse. It is unclear which epigenetic features maintain stem-cell properties, restrict adult expression of fetal genes, and are attenuated in tumours, allowing non-stem cells to replenish targeted tumour stem cells. Here we show that reversible stemness in normal adult intestinal crypt cells hinges on a dynamic balance between activating H3K27ac and repressive H3K27me3 marks. Cells that leave the Wnt-rich stem-cell niche normally acquire H3K27me3 at thousands of stemness-associated enhancers. Constitutive tumourigenic Wnt activity transforms Apc-/- intestinal stem cells by gradual erosion of H3K27me3 at select enhancers and extends stem-like properties beyond usual anatomic confines; continued depletion of H3K27me3 reactivates enhancers that control growth and expression of a wider swath of fetal genes than appreciated previously. Subsequent focal DNA demethylation at expanded superenhancer domains is associated with tumour growth. Human colorectal cancers also carry evidence of this epigenetic rewiring. Accelerated H3K27me3 loss in mice hastens, and its preservation delays, activation of stemness-related enhancers, superenhancers, and tumour progression. During transformation, H3K27me3 loss at enhancers erases a crucial distinction between stem and non-stem populations, endowing the latter with stemness and providing an explanation for tumour resistance to cancer stem cell targeting. Thus, H3K27me3 at Wnt-responsive enhancers is an intrinsic barrier to intestinal tumourigenesis and aberrant reactivation of hundreds of fetal genes.

cancer biology↗

bioRxiv2024

DNA methylation-dependent and -independent binding of CDX2 directs activation of distinct developmental and homeostatic genes

Precise spatiotemporal and cell type-specific gene expression is essential for proper tissue development and function. Transcription factors (TFs) guide this process by binding to developmental stage-specific targets and establishing an appropriate enhancer landscape. In turn, DNA and chromatin modifications direct the genomic binding of TFs. However, how TFs navigate various chromatin features and selectively bind a small portion of the millions of possible genomic target loci is still not well understood. Here we show that Cdx2 - a pioneer TF that binds distinct targets in developing versus adult intestinal epithelial cells - has a preferential affinity for a non-canonical CpG-containing motif in vivo. A higher frequency of this motif at embryonic and fetal Cdx2 target loci and the specifically methylated state of the CpG during development allows selective Cdx2 binding and activation of developmental enhancers and linked genes. Conversely, demethylation at these enhancers prohibits ectopic Cdx2 binding in adult cells, where Cdx2 binds its canonical motif without a CpG. This differential Cdx2 binding allows for corecruitment of Ctcf and Hnf4, facilitating the establishment of intestinal superenhancers during development and enhancers mediating adult homeostatic functions, respectively. Induced gain of DNA methylation in the adult mouse epithelium or cultured cells causes ectopic recruitment of Cdx2 to the developmental target loci and facilitates cobinding of the partner TFs. Together, our results demonstrate that the differential CpG motif requirements for Cdx2 binding to developmental versus adult target sites allow it to navigate different DNA methylation profiles and activate cell type-specific genes at appropriate times. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/579850v3_ufig1.gif" ALT="Figure 1"> View larger version (99K): org.highwire.dtl.DTLVardef@12d2253org.highwire.dtl.DTLVardef@289371org.highwire.dtl.DTLVardef@1e81b4borg.highwire.dtl.DTLVardef@157e322_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2019

Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs

Lifelong production of the many types of mature blood cells from less differentiated progenitors is a hierarchically ordered process that spans multiple cell divisions. The nature and timing of the molecular events required to integrate the environmental signals, transcription factor activity, epigenetic modifications, and changes in gene expression involved are thus complex and still poorly understood. We now show that the more primitive types of human cells in this system display a unique repressive H3K27me3 signature that is retained by mature lymphoid cells but is lost in terminally differentiated monocytes and erythroblasts. Additional intervention data implicate that control of this chromatin state change is a requisite part of the process, whereby normal human hematopoietic progenitor cells make lymphoid and myeloid fate decisions.

cell biology↗