TY - JOUR
T1 - Suv39h-catalyzed H3K9me3 is critical for euchromatic genome organization and the maintenance of gene transcription
AU - Keenan, Christine R.
AU - Coughlan, Hannah D.
AU - Iannarella, Nadia
AU - del Fierro, Andres Tapia
AU - Keniry, Andrew
AU - Johanson, Timothy M.
AU - Chan, Wing Fuk
AU - Garnham, Alexandra L.
AU - Whitehead, Lachlan W.
AU - Blewitt, Marnie E.
AU - Smyth, Gordon K.
AU - Allan, Rhys S.
N1 - Funding Information:
We thank Thomas Jenuwein (MPI, Frieburg) for the Suv39h-deficient mice (Peters et al. 2001). We acknowledge the tremendous technical assistance from the staff of the core facilities at the Walter and Eliza Hall Institute, particularly Stephen Wilcox and Sarah MacRaild in the WEHI genomics hub, the staff of the Flow Cytometry facility (WEHIFACS), and WEHI Bioservices. This work was supported by grants and fellowships from the National Health and Medical Research Council (NHMRC) of Australia (C.R.K. and H.D.C.: 2010571; C.R.K.: 1125436; T.M.J.: 1124081; R.S.A.: 1100451, 1158531, 2001131; G.K.S.: 1154970), and the Australian Research Council (R.S.A.: 130100541). H.D.C. was supported by the Marian and E.H. Flack fellowship. This study was made possible through the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme. Author contributions: C.R.K., N.I., A.T.d.F., A.K., T.M.J., and W.F.C. performed experiments. H.D.C., A.L.G., and L.W.W. performed formal analysis. M.E.B. provided critical resources. C.R.K., H.D.C., and R.S.A. wrote the paper. G.K.S. and R.S.A. supervised the research.
Funding Information:
We thank Thomas Jenuwein (MPI, Frieburg) for the Suv39h-deficient mice (Peters et al. 2001). We acknowledge the tremendous technical assistance from the staff of the core facilities at the Walter and Eliza Hall Institute, particularly Stephen Wilcox and Sarah MacRaild in the WEHI genomics hub, the staff of the Flow Cytometry facility (WEHIFACS), and WEHI Bioservices. This work was supported by grants and fellowships from the National Health and Medical Research Council (NHMRC) of Australia (C.R.K. and H.D.C.: 2010571; C.R.K.: 1125436; T.M.J.: 1124081; R.S.A.: 1100451, 1158531, 2001131; G.K.S.: 1154970), and the Australian Research Council (R.S.A.: 130100541). H.D.C. was supported by the Marian and E.H. Flack fellowship. This study was made possible through the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme.
Publisher Copyright:
© 2024 Keenan et al.
PY - 2024
Y1 - 2024
N2 - 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 catalyze heterochromatic H3K9me3 deposition. We reveal a paradoxical repression of protein-coding genes in Suv39DKO cells, with these differentially expressed genes principally in euchromatic (Tn5-accessible, H3K4me3- and H3K27ac-marked) rather than heterochromatic (H3K9me3-marked) or polycomb (H3K27me3-marked) regions. Examination of the three-dimensional (3D) nucleome reveals that transcriptomic dysregulation occurs in euchromatic regions close to the nuclear periphery in 3D space. Moreover, this transcriptomic dysregulation is highly correlated with altered 3D 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 organization and the maintenance of gene transcription for healthy cellular function.
AB - 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 catalyze heterochromatic H3K9me3 deposition. We reveal a paradoxical repression of protein-coding genes in Suv39DKO cells, with these differentially expressed genes principally in euchromatic (Tn5-accessible, H3K4me3- and H3K27ac-marked) rather than heterochromatic (H3K9me3-marked) or polycomb (H3K27me3-marked) regions. Examination of the three-dimensional (3D) nucleome reveals that transcriptomic dysregulation occurs in euchromatic regions close to the nuclear periphery in 3D space. Moreover, this transcriptomic dysregulation is highly correlated with altered 3D 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 organization and the maintenance of gene transcription for healthy cellular function.
UR - http://www.scopus.com/inward/record.url?scp=85193459389&partnerID=8YFLogxK
U2 - 10.1101/gr.279119.124
DO - 10.1101/gr.279119.124
M3 - Article
C2 - 38719473
AN - SCOPUS:85193459389
SN - 1088-9051
VL - 34
SP - 556
EP - 571
JO - Genome Research
JF - Genome Research
IS - 4
ER -