Introduction

Modern chicken breeds dissipate considerable body heat and are sensitive to heat stress due to genetic selection for heightened metabolic activity and meat and egg production1,2. Heat stress leads to adverse alterations of behavioral, physiological, reproductive, and immunological responses, causing significant reduction in feed intake, body weight gain, egg production, and meat and egg quality2,3,4,5,6,7. Diminished growth, disease susceptibility, and high mortality resulting from heat stress account for a large part of the cost of poultry production throughout the world8.

When a behavioral response fails to meet heat loss requirements under a high ambient temperature, the sympathetic–adrenal–medullary axis (SAM axis) and the hypothalamus–pituitary–adrenal axis (HPA axis) are activated to compensate for the thermal imbalance9. Catecholamine (e.g., epinephrine and norepinephrine) and glucocorticoid (GC) release from the SAM axis and HPA axis enhance hepatic glycogenolysis and gluconeogenesis to supply more glucose for energy need in heat stress alleviation10,11.

Proteomics is a powerful tool for improving genetic selection, and has been applied in exploring the biological mechanisms of different tissues in response to heat stress67 for protein expression and histone modification analysis.

Plasma epinephrine and corticosterone analysis

Plasma epinephrine and corticosterone (CORT) levels were measured using Adrenaline Research ELISA (BA E-5100, ImmuSmol SAS, Bordeaux, France) and the Corticosterone ELISA Kit (501,320, Cayman Chemical, Ann Arbor, MI, USA), respectively.

Protein sample preparation, isobaric tags for relative and absolute quantitation (iTRAQ) analysis, and fractionation of peptides

The collected adrenal glands were sliced into small pieces and lysed in O’Farrell’s lysis buffer (9.5 M urea, 65 mM dithiothreitol, 2% v/v Ampholyte 3–10, and 2% NP-40). The samples were sonicated (80 W; four times for 10 s) to dissolute proteins. The homogenates were maintained at 4 °C for 1 h and centrifuged at 14,000 × g at 4 °C for 10 min to obtain supernatants. The supernatants were mixed with 100% trichloroacetic acid (TCA) to obtain a final TCA concentration of 20% and maintained at 4 °C for 1 h with shaking every 15 min. After centrifugation at 14,000 g at 4 °C for 10 min, the precipitated pellets were collected and washed with ice-cold acetone twice. The protein pellets were air-dried for 10 min and dissolved in 4 M urea solution. Protein concentrations were determined using the Bradford method with bovine serum albumin as the standard68.

This study performed iTRAQ labeling according to the manufacturer’s protocol (iTRAQ reagent multiplex kit, Applied Biosystems, Waltham, MA, USA). Five replicated protein samples from the same group were mixed and used for reduction and alkylation, which was followed by overnight digestion with trypsin. The tryptic peptides from the control, resistant, and susceptible groups were labeled with isobaric iTRAQ tags with mass 114, 115, and 116 Da, respectively. The samples were then pooled, dried using a SpeedVac evaporator (Tokyo Rikakikai Co. Ltd., Bunkyo-ku, Tokyo, Japan), and stored at − 80 °C until analysis.

Fractionation of the labeled peptides was performed using an ultraperformance liquid chromatography (UPLC) system (ACQUITY UPLC System, Waters, Milford, MA, USA) and a 2.1 mm × 150 mm × 1.7 µm column with a volume of 0.519 mL (ACQUITY UPLC BEH C18, Waters). The mobile phase was prepared in a gradient with 10 mM ammonium bicarbonate (ABC, pH 10, mobile phase A) and 10 mM ABC/90% acetonitrile (pH 10, mobile phase B). A gradient was created with mobile phase B from 0 to 3% during min 0–5; 3% to 30% during min 5–40; 30% to 70% during min 40–55; and 70% to 0% during min 55–60. The flow rate was 0.2 µL/min. Fractions were collected in 1-min intervals for 1 h duration. Urea solutions in various fractions were removed using C18 ZipTip (Merck, Darmstadt, Germany). All fractions were dried using a SpeedVac evaporator (Tokyo Rikakikai Co. Ltd.) and stored at − 80 °C until analysis.

Protein identification using nano-UPLC–electrospray ionization (ESI)–quadruple time-of-flight (Q-TOF)–MS/MS

A nano-LC–MS/MS system was used to analyze the tryptic peptides. The peptides were separated using an Ultimate 3000 LC RSLC nano-LC system (Dionex-Thermo Scientific, Chelmsford, MA, USA) coupled with a Q-TOF mass spectrometer (ma** column (Acclaim PepMap C18, Dionex-Thermo Scientific) connected to a C18 analyst column (Acclaim PepMap C18, Dionex-Thermo Scientific) for peptide separation. The labeled peptides were eluted using a linear gradient of mobile phase A (2% ACN and 0.1% FA) and mobile phase B (80% ACN and 0.1% FA) applied at a flow rate of 0.3 µL/min for 90 min. The gradient conditions were as follows: 5% to 30% mobile phase B during min 5–65; 30% to 98% mobile phase B during min 65–79, and finally, down to 10% mobile phase B within 1 min.

The mass spectrometer was operated at 50–2000 m/z at 2 Hz, and the 20 most intense ions with 420–2000 m/z in each survey scan were selected for the MS/MS experiment. MS/MS data were acquired from 50 to 2000 m/z at 5–10 Hz. The MS/MS spectra were de novo sequenced and assigned a protein ID by using PEAKS X (Version X, ; Bioinformatics Solutions, Waterloo, Canada) and searched against the NCBInr database (NCBInr 20,180,904 version) for protein identification. The false discovery rate (FDR) of peptide identification was set to be less than 1%. Protein quantification was achieved using PEAKS X with a significant score (− 10logP) > 15 equal to a P-value < 0.03 using FDR-corrected peaks, and at least one unique peptide was detected. Totally, 80 DEPs were identified and quantified using iTRAQ analysis with a 1.3-fold change for a high (> 1.3) or low (< 0.77) level of relative abundance being considered as differentially expressed proteins (DEPs) of the upregulation or downregulation between the two compared groups, respectively. The volcano diagrams and hierarchical clustering of DEPs were generated by PEAKS X software (Bioinformatics Solutions).

Bioinformatics analysis of DEPs

The DEPs among the groups were annotated for their cellular components, biological processes, and molecular functions by using the Gene Ontology database (amigo1.geneontology.org/cgi-bin/amigo/go.cgi).

Western blot analysis

In electrophoresis for protein separation, each well contained a respective sample with 50 µg of proteins. Proteins were transferred onto PVDF (polyvinylidene fluoride) membrane through the wet-transfer method. A mouse anti-HSP70 (clone N27F3-4) monoclonal antibody was purchased from Enzo Life Sciences (New York, USA). A mouse anti-GAPDH (clone 1D4) monoclonal antibody was purchased from Novus Biologicals (Denver, USA). Horseradish peroxidase conjugated secondary antibodies; goat anti-mouse IgG (Beckman Coulter, Brea, CA, USA) was used for to identify the bands reactive to the primary antibodies through an enhanced chemiluminescence reagent (Pierce Biotechnology Inc., Rockford, IL, USA). Primary and secondary antibodies were incubated with membranes at 1:1000 and 1:5000 dilation, respectively. Signaling was quantified by the luminescence image analyzer ImageQuant LAS 4000 (GE Healthcare Life Sciences).

Histone sample preparation, chemical derivatization, trypsin digestion, and desalting

Histones were isolated using a modified protocol69. Briefly, nuclei were isolated with nuclei isolation buffer (NIB; 15 mM Tris, 60 mM KCl, 15 mM NaCl, 5 mM MgCl2, 1 mM CaCl2, and 250 mM sucrose and protease inhibitor cocktail tablet; pH 7.5) and 0.2% NP-40. After they had been cut into small pieces, the adrenal glands in NIB were homogenized using a homogenizer (T 10 basic ULTRA-TURRAX, IKA, Guangzhou, China), which was followed by 10 min incubation on ice. The mixture was centrifuged at 1,000 × g at 4 °C for 10 min, and the resultant nuclei pellets were collected. The pellets were washed with NIB twice. Histones were then acid-extracted from the isolated nuclei by using 0.2 M H2SO4 at 4 °C for 4 h with shaking every 15 min. The histone-containing supernatants were mixed with 100% TCA to a final TCA concentration of 33% and incubated on ice for 1 h. The histone-enriched pellets were washed with ice-cold acetone/0.1% hydrochloric acid and ice-cold acetone and centrifuged to enable pellet collection. The collected pellets were air-dried and reconstituted in double-distilled water. Finally, the histones were purified through centrifugation and quantified for concentration by using the Bradford method with bovine serum albumin as the standard (Peterson, 1983). All samples were dried using a SpeedVac evaporator (Tokyo Rikakikai Co. Ltd.) and dissolved in 40 μL of 50 mM ammonium bicarbonate, which had pH 8 (concentration > 1 μg/μL). Histones were prepared for MS analysis through propionic anhydride chemical derivatization, trypsin digestion, and propionylation of histone peptides at N-termini, as was described by Sidoli et al. (2016). Then, all histone peptides were desalted with C18 ZipTip (Merck), dried using the SpeedVac evaporator, and finally stored at − 80 °C until analysis.

Identification of histone modifications by using nano-UPLC-ESI-Q-TOF–MS/MS

Nano-LC–MS/MS and the protocol for identification of histone modifications were performed as is described in “Acute heat stress modulates adrenal HPTMs” section. Briefly, histone peptides dissolved in 10 µL of loading buffer were separated and eluted using a linear gradient of mobile phase A (2% ACN, 0.1% FA) and mobile phase B (80% ACN, 0.1% FA) applied at a flow rate of 0.3 µL/min for 90 min. The gradient conditions were as follows: 10% to 40% mobile phase B at min 6–74, 40% to 99% mobile phase B at min 74.1–79, and finally, down to 10% mobile phase B within 1 min.

The MS parameters were as described in “Acute heat stress modulates adrenal HPTMs” section. Label-free quantification was performed using the quantitation module of PEAKS X. Modified histone peptides were identified using PEAKS X through the following search parameters: parent mass error tolerance: 80.0 ppm; fragment mass error tolerance: 0.07 Da; enzyme: trypsin; maximum number of missed cleavages: 2; digestion mode: specific; fixed modifications: propionyl (N-term): 56.0; variable modifications: oxidation (M): 15.99, acetylation (K): 42.01, dimethylation (K): 28.03, methylation (K): 14.02, trimethylation (K): 42.05, propionyl (K): 56.03, deamidation (NQ): 0.98, propionylmethyl: 70.04; maximum number of variable PTMs per peptide: 9; reported number of peptides: 5; and data refine dependencies: 1, 4, 3, 2, 5, 6, 7, 8, 9, 10, 11, 12, 14, 13, 15, 16, 17, 19, 18, and 20. The quantification of histone modification was performed using the PEAKS DB database, which provided an overview of all peptides and histone modifications. The relative abundance of a given PTM resulting from single- or co-occurring PTMs was calculated by dividing its intensity by the sum of intensities for all modified and unmodified peptides sharing the same sequence and without missing values. Therefore, the given PTMs could have only a single datum. The quantification of each peptide of co-occurring PTMs on histone H3 was divided by the quantification of all modified and unmodified peptides to obtain a relative quantification of the histone H3 peptide and the crosstalk of PTMs on histone H3.

Statistical analysis

The concentrations of plasma epinephrine and CORT were analyzed using Student’s t test in the Statistical Analysis System (SAS) software70. The normality of the body temperature changes, western blot analysis and relative values of DEPs and HPTMs were assessed using the normality test. Normally distributed data were analyzed using the least squares means procedure, whereas non-normally distributed data were analyzed using the Kruskal–Wallis test.