PMID- 38519987
OWN - NLM
STAT- MEDLINE
DCOM- 20240325
LR  - 20240401
IS  - 1474-760X (Electronic)
IS  - 1474-7596 (Print)
IS  - 1474-7596 (Linking)
VI  - 25
IP  - 1
DP  - 2024 Mar 22
TI  - Depletion of lamins B1 and B2 promotes chromatin mobility and induces 
      differential gene expression by a mesoscale-motion-dependent mechanism.
PG  - 77
LID - 10.1186/s13059-024-03212-y [doi]
LID - 77
AB  - BACKGROUND: B-type lamins are critical nuclear envelope proteins that interact 
      with the three-dimensional genomic architecture. However, identifying the direct 
      roles of B-lamins on dynamic genome organization has been challenging as their 
      joint depletion severely impacts cell viability. To overcome this, we engineered 
      mammalian cells to rapidly and completely degrade endogenous B-type lamins using 
      Auxin-inducible degron technology. RESULTS: Using live-cell Dual Partial Wave 
      Spectroscopic (Dual-PWS) microscopy, Stochastic Optical Reconstruction Microscopy 
      (STORM), in situ Hi-C, CRISPR-Sirius, and fluorescence in situ hybridization 
      (FISH), we demonstrate that lamin B1 and lamin B2 are critical structural 
      components of the nuclear periphery that create a repressive compartment for 
      peripheral-associated genes. Lamin B1 and lamin B2 depletion minimally alters 
      higher-order chromatin folding but disrupts cell morphology, significantly 
      increases chromatin mobility, redistributes both constitutive and facultative 
      heterochromatin, and induces differential gene expression both within and near 
      lamin-associated domain (LAD) boundaries. Critically, we demonstrate that 
      chromatin territories expand as upregulated genes within LADs radially shift 
      inwards. Our results indicate that the mechanism of action of B-type lamins comes 
      from their role in constraining chromatin motion and spatial positioning of 
      gene-specific loci, heterochromatin, and chromatin domains. CONCLUSIONS: Our 
      findings suggest that, while B-type lamin degradation does not significantly 
      change genome topology, it has major implications for three-dimensional chromatin 
      conformation at the single-cell level both at the lamina-associated periphery and 
      the non-LAD-associated nuclear interior with concomitant genome-wide 
      transcriptional changes. This raises intriguing questions about the individual 
      and overlapping roles of lamin B1 and lamin B2 in cellular function and disease.
CI  - (c) 2024. The Author(s).
FAU - Pujadas Liwag, Emily M
AU  - Pujadas Liwag EM
AUID- ORCID: 0000-0002-3520-835X
AD  - Department of Biomedical Engineering, Northwestern University, Evanston, IL, 
      60208, USA.
AD  - IBIS Interdisciplinary Biological Sciences Graduate Program, Northwestern 
      University, Evanston, USA.
AD  - Center for Physical Genomics and Engineering, Northwestern University, Evanston, 
      IL, 60208, USA.
FAU - Wei, Xiaolong
AU  - Wei X
AD  - Department of Surgery, University of Virginia School of Medicine, 
      Charlottesville, VA, 22903, USA.
FAU - Acosta, Nicolas
AU  - Acosta N
AD  - Department of Biomedical Engineering, Northwestern University, Evanston, IL, 
      60208, USA.
AD  - Center for Physical Genomics and Engineering, Northwestern University, Evanston, 
      IL, 60208, USA.
FAU - Carter, Lucas M
AU  - Carter LM
AD  - Department of Biomedical Engineering, Northwestern University, Evanston, IL, 
      60208, USA.
AD  - IBIS Interdisciplinary Biological Sciences Graduate Program, Northwestern 
      University, Evanston, USA.
AD  - Center for Physical Genomics and Engineering, Northwestern University, Evanston, 
      IL, 60208, USA.
FAU - Yang, Jiekun
AU  - Yang J
AD  - Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute 
      of Technology, Cambridge, MA, 02139, USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
FAU - Almassalha, Luay M
AU  - Almassalha LM
AD  - Department of Biomedical Engineering, Northwestern University, Evanston, IL, 
      60208, USA.
AD  - Center for Physical Genomics and Engineering, Northwestern University, Evanston, 
      IL, 60208, USA.
AD  - Department of Gastroenterology and Hepatology, Northwestern Memorial Hospital, 
      Chicago, IL, 60611, USA.
FAU - Jain, Surbhi
AU  - Jain S
AD  - Department of Biomedical Engineering, Northwestern University, Evanston, IL, 
      60208, USA.
AD  - Center for Physical Genomics and Engineering, Northwestern University, Evanston, 
      IL, 60208, USA.
FAU - Daneshkhah, Ali
AU  - Daneshkhah A
AD  - Department of Biomedical Engineering, Northwestern University, Evanston, IL, 
      60208, USA.
AD  - Center for Physical Genomics and Engineering, Northwestern University, Evanston, 
      IL, 60208, USA.
FAU - Rao, Suhas S P
AU  - Rao SSP
AD  - The Center for Genome Architecture, Baylor College of Medicine, Houston, TX, 
      77030, USA.
AD  - School of Medicine, Stanford University, Stanford, CA, 94305, USA.
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 
      TX, 77030, USA.
FAU - Seker-Polat, Fidan
AU  - Seker-Polat F
AD  - Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department 
      of Obstetrics and Gynecology, Northwestern University, Chicago, IL, 60611, USA.
FAU - MacQuarrie, Kyle L
AU  - MacQuarrie KL
AD  - Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department 
      of Pediatrics, Northwestern University, Chicago, IL, 60611, USA.
AD  - Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's 
      Hospital of Chicago, Chicago, IL, USA.
FAU - Ibarra, Joe
AU  - Ibarra J
AD  - Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department 
      of Pediatrics, Northwestern University, Chicago, IL, 60611, USA.
AD  - Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's 
      Hospital of Chicago, Chicago, IL, USA.
FAU - Agrawal, Vasundhara
AU  - Agrawal V
AD  - Department of Biomedical Engineering, Northwestern University, Evanston, IL, 
      60208, USA.
AD  - Center for Physical Genomics and Engineering, Northwestern University, Evanston, 
      IL, 60208, USA.
FAU - Aiden, Erez Lieberman
AU  - Aiden EL
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
AD  - The Center for Genome Architecture, Baylor College of Medicine, Houston, TX, 
      77030, USA.
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 
      TX, 77030, USA.
AD  - Center for Theoretical Biological Physics, Rice University, Houston, TX, 77030, 
      USA.
AD  - Departments of Computer Science and Computational and Applied Mathematics, Rice 
      University, Houston, TX, 77030, USA.
FAU - Kanemaki, Masato T
AU  - Kanemaki MT
AD  - Department of Chromosome Science, National Institute of Genetics, Mishima, 
      Shizuoka, 411-8540, Japan.
AD  - Graduate Institute for Advanced Studies, SOKENDAI, Mishima, Shizuoka, 411-8540, 
      Japan.
AD  - Department of Biological Science, The University of Tokyo, Tokyo, 113-0033, 
      Japan.
FAU - Backman, Vadim
AU  - Backman V
AD  - Department of Biomedical Engineering, Northwestern University, Evanston, IL, 
      60208, USA. v-backman@northwestern.edu.
AD  - Center for Physical Genomics and Engineering, Northwestern University, Evanston, 
      IL, 60208, USA. v-backman@northwestern.edu.
FAU - Adli, Mazhar
AU  - Adli M
AD  - Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department 
      of Obstetrics and Gynecology, Northwestern University, Chicago, IL, 60611, USA. 
      adli@northwestern.edu.
LA  - eng
GR  - RM1HG011016-01A1/HG/NHGRI NIH HHS/United States
GR  - U54 CA268084/NH/NIH HHS/United States
GR  - T32AI083216/NH/NIH HHS/United States
GR  - T32 AI083216/AI/NIAID NIH HHS/United States
GR  - 5 UM1 HG012649/NH/NIH HHS/United States
GR  - RM1 HG011016/HG/NHGRI NIH HHS/United States
GR  - U54CA261694/NH/NIH HHS/United States
GR  - R01CA228272/NH/NIH HHS/United States
GR  - UM1HG009375/NH/NIH HHS/United States
PT  - Journal Article
DEP - 20240322
PL  - England
TA  - Genome Biol
JT  - Genome biology
JID - 100960660
RN  - 0 (Chromatin)
RN  - 0 (Lamin Type B)
RN  - 0 (Heterochromatin)
RN  - 0 (Lamin Type A)
RN  - 0 (Lamins)
SB  - IM
UOF - bioRxiv. 2023 Jun 26;:. PMID: 37425796
MH  - Animals
MH  - *Chromatin
MH  - *Lamin Type B/genetics
MH  - Heterochromatin
MH  - In Situ Hybridization, Fluorescence
MH  - Lamin Type A/genetics/metabolism
MH  - Lamins
MH  - Gene Expression
MH  - Mammals/genetics
PMC - PMC10958841
OTO - NOTNLM
OT  - 3D chromatin organization
OT  - Auxin-inducible degron system
OT  - CRISPR-Sirius; in situ Hi-C
OT  - Lamin-associated domains
OT  - Nuclear lamina
OT  - Partial Wave Spectroscopic Microscopy
OT  - Topologically associated domains
COIS- The authors declare that they have no competing interests.
EDAT- 2024/03/23 20:43
MHDA- 2024/03/25 06:44
PMCR- 2024/03/22
CRDT- 2024/03/23 01:29
PHST- 2023/06/05 00:00 [received]
PHST- 2024/03/07 00:00 [accepted]
PHST- 2024/03/25 06:44 [medline]
PHST- 2024/03/23 20:43 [pubmed]
PHST- 2024/03/23 01:29 [entrez]
PHST- 2024/03/22 00:00 [pmc-release]
AID - 10.1186/s13059-024-03212-y [pii]
AID - 3212 [pii]
AID - 10.1186/s13059-024-03212-y [doi]
PST - epublish
SO  - Genome Biol. 2024 Mar 22;25(1):77. doi: 10.1186/s13059-024-03212-y.