The nucleus, a cell's command center, houses DNA and orchestrates genetic activities. Its double-membrane envelope, perforated by nuclear pores, acts as a gatekeeper, controlling molecular traffic between the nucleus and cytoplasm. This selective barrier maintains distinct environments crucial for cellular functions.

Inside the nucleus, chromatin organization plays a key role in gene expression. Euchromatin, less condensed and more accessible, allows active transcription. Heterochromatin, tightly packed, represses gene activity. This dynamic structure influences how genes are read and expressed, shaping cellular behavior.

Nucleus and Nuclear Envelope

Structure and function of nucleus

• Nucleus largest organelle in eukaryotic cells contains genetic material (DNA) and nucleoli
  • Surrounded by double-membrane nuclear envelope
    • Outer membrane continuous with endoplasmic reticulum (ER)
    • Inner membrane lined with nuclear lamina provides structural support
  • Nuclear pore complexes perforate nuclear envelope regulate transport of molecules between nucleus and cytoplasm
• Nucleolus dense, non-membrane bound structure within nucleus site of ribosomal RNA (rRNA) synthesis and ribosome subunit assembly
• Chromatin DNA and associated proteins (histones) within nucleus
  • Euchromatin less condensed, transcriptionally active (genes actively expressed)
  • Heterochromatin highly condensed, transcriptionally inactive (genes repressed)

Role of nuclear envelope

• Nuclear envelope acts as selective barrier controls entry and exit of molecules between nucleus and cytoplasm maintains distinct nuclear and cytoplasmic environments
• Nuclear pore complexes (NPCs) mediate transport
  1. Allow passive diffusion of small molecules (ions, metabolites)
  2. Facilitate active transport of larger molecules (proteins, RNA) through nuclear localization signals (NLS) or nuclear export signals (NES)
• Ran GTPase gradient drives directional transport
  • Ran-GTP (nucleus) and Ran-GDP (cytoplasm) gradient
    • Importins bind cargo with NLS in cytoplasm release it in nucleus upon Ran-GTP binding
    • Exportins bind cargo with NES in nucleus release it in cytoplasm upon Ran-GTP hydrolysis

Proteins in nuclear pore complexes

• Nucleoporins (Nups) building blocks of NPCs over 30 different Nups in vertebrates (humans)
  • Structural Nups provide scaffold maintain NPC architecture (Nup107-160 complex, Nup93 complex)
  • FG-Nups contain phenylalanine-glycine (FG) repeats form selective permeability barrier interact with transport receptors (Nup98, Nup153, Nup214)
  • Transmembrane Nups anchor NPCs to nuclear envelope (Pom121, Ndc1, gp210)
• Ran GTPase and its regulators drive directional transport
  • Ran small GTPase
  • RCC1 Ran guanine nucleotide exchange factor (GEF) generates Ran-GTP in nucleus
  • RanGAP Ran GTPase-activating protein stimulates Ran-GTP hydrolysis in cytoplasm

Chromatin organization and gene expression

• Chromatin organization DNA wrapped around histone octamers forms nucleosomes further compacts into higher-order structures (chromatin fibers, loops, domains)
  • Euchromatin less condensed, more accessible enriched in actively transcribed genes associated with histone modifications that promote transcription (H3K4me3, H3K36me3)
  • Heterochromatin highly condensed, less accessible contains fewer actively transcribed genes associated with histone modifications that repress transcription (H3K9me3, H3K27me3)
• Chromatin remodeling complexes alter chromatin accessibility by repositioning, evicting, or exchanging nucleosomes (SWI/SNF, ISWI, CHD, INO80 families)
• Chromatin accessibility influences transcription factor binding and gene expression
  • Open chromatin (euchromatin) facilitates transcription factor access and gene activation
  • Closed chromatin (heterochromatin) hinders transcription factor access and gene repression
• Nuclear bodies distinct nuclear domains associated with specific functions
  • Cajal bodies involved in snRNP biogenesis
  • PML bodies involved in transcription and apoptosis
  • Nuclear speckles involved in pre-mRNA splicing