Biology subjects

Iannarella, N.

Publications and source records attributed to Iannarella, N..

5 recordsLinked to original sources

bioRxiv2026

Multi-omic gene regulatory networks informed by 3D chromatin architecture reveal insights into hematopoietic stem cell ageing

During ageing, hematopoietic stem cells (HSCs) have reduced regenerative potential, skewed differentiation toward the myeloid lineage, and heightened susceptibility to clonal expansion and malignancy. While epigenetic alterations are well documented, the impact of aging on higher-order 3D chromatin architecture remains poorly understood. Here, we examined the 3D genome organisation of aged murine HSCs using in-situ Hi-C then integrated this with gene expression and chromatin accessibility data to build HiC-informed gene regulatory networks (GRNs). Aged HSCs display erosion of topologically associating domain (TAD) boundaries, A/B compartment switching, and reorganised enhancer-promoter loops associated with lineage-inappropriate gene expression. Our GRN analysis identifies a hierarchy of transcription factors, including a c-Maf-Lyl1-Mnt axis that orchestrates the transition from a youthful to aged state and a Gfi1-Sox4 axis in young HSCs that regulates Bach1. This study provides a structural blueprint for aging HSCs and defines specific regulatory targets for potential reprogramming interventions to restore hematopoietic youthfulness.

immunology↗

bioRxiv2025

The long non-coding RNA Dreg1 is required for optimal ILC2 development

Gata3 is an essential transcription factor for the development of several distinct immune cell lineages such as T cells, natural killer (NK) cells and innate lymphoid cells (ILC). As such, the levels and timing of Gata3 expression are critical for directing lineage fate decisions. The Gata3 locus has a complex and dynamic distal regulatory enhancer landscape. Recently we identified a non-coding RNA, Dreg1, located immediately upstream of the classic +280kb T/NK cell enhancer (Tce1). To test its function, we excised the Dreg1 locus in mice and observed a selective reduction of group 2 ILCs (ILC2) across multiple tissues, but mature T, NK and other ILC lineages remained unchanged. In bone marrow, common innate lymphoid cell progenitors (ILCP) increased while ILC2 progenitors (ILC2P) decreased, with a modest reduction of Gata3 in upstream progenitors consistent with an early developmental bottleneck. Chromatin profiling showed the Dreg1 locus is accessible in early lymphoid progenitors and became decorated with H3K27ac in ILCP in a Tcf1-dependent manner. Furthermore, Tcf1-deficient cells did not express Dreg1 and showed alterations in the epigenetic landscape of the Dreg1 locus. Finally, we discovered that potential homologues of Dreg1 harboured in a syntenic enhancer of GATA3 are also highly expressed in human ILC2. Taken together we conclude that Dreg1 is a Tcf1-dependent non-coding RNA critical for fine tuning the high level of Gata3 required for the optimal development of the ILC2 lineage.

immunology↗

bioRxiv2022

Survey of activation-induced genome architecture reveals a novel enhancer of Myc

The transcription factor Myc is critically important in driving cell proliferation, a function that is frequently dysregulated in cancer. To avoid this dysregulation Myc is tightly controlled by numerous layers of regulation. One such layer is the use of distal regulatory enhancers to drive Myc expression. Here, using chromosome conformation capture to examine B cells of the immune system in the first hours after their activation, we reveal a previously unidentified enhancer of myc. The interactivity of this enhancer coincides with a dramatic, but discrete, spike in Myc expression 3 hours post-activation. However, genetic deletion of this region, has little impact on Myc expression, Myc protein level or in vitro and in vivo cell proliferation. Examination of the enhancer deleted regulatory landscape suggests that enhancer redundancy likely sustains Myc expression. This work highlights not only the importance of temporally examining enhancers, but also the complexity and dynamics of the regulation of critical genes such as Myc.

genetics↗

bioRxiv2022

CIS calibrates GM-CSF signalling strength to regulate macrophage polarization via a STAT5-IRF8 axis

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the ability to differentiate macrophages (MOs) with opposing functions, namely proinflammatory M1-like and immunosuppressive M2-like. Despite the importance and opposing functional outcomes of these processes, the intrinsic mechanism that regulates the functional polarization of MOs under GM-CSF signaling remains elusive. Here we show that GM-CSF induced MOs polarisation resulted in the expression of the Cytokine-inducible SH2-containing protein (CIS), and that CIS deficiency diverted differentiation of monocytes into immunosuppressive M2-like MOs expression. CIS deficiency resulted in the hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting the downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss and gain of function approaches highlighted IRF8 as a critical instructor of the M1-like polarisation program. In vivo, CIS deficiency led to skewing to M2-like macrophages, which induced strong Th2 immune responses characterised by the development of severe experimental asthma. Collectively, we reveal a CIS-censored mechanism interpreting the opposing actions of GM-CSF in MO differentiation and uncovering its role in controlling allergic inflammation.

immunology↗

bioRxiv2020

Suv39h-catalysed H3K9me3 is critical for euchromatic genome organisation and the maintenance of gene transcription

H3K9me3-dependent heterochromatin is critical for the silencing of repeat-rich pericentromeric regions and also has key roles in repressing lineage-inappropriate protein-coding genes in differentiation and development. Here, we investigate the molecular consequences of heterochromatin loss in cells deficient in both Suv39h1 and Suv39h2 (Suv39DKO), the major mammalian histone methyltransferase enzymes that catalyse heterochromatic H3K9me3 deposition. Unexpectedly, we reveal a predominant repression of protein-coding genes in Suv39DKO cells, with these differentially expressed genes principally in euchromatic (DNaseI-accessible, H3K27ac-marked) rather than heterochromatic (H3K9me3-marked) regions. Examination of the 3D nucleome reveals that transcriptomic dysregulation occurs in euchromatic regions close to the nuclear periphery in 3-dimensional space. Moreover, this transcriptomic dysregulation is highly correlated with altered 3-dimensional genome organization in Suv39DKO cells. Together, our results suggest that the nuclear lamina-tethering of Suv39-dependent H3K9me3 domains provides an essential scaffold to support euchromatic genome organisation and the maintenance of gene transcription for healthy cellular function.

genomics↗